Chemical Compounds

ABSTRACT

The invention is directed to substituted piperidine derivatives. Specifically, the invention is directed to compounds according to Formula IIII: 
     
       
         
         
             
             
         
       
     
     wherein A, B, X, Y, L 1 , L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , z 2 , z 4 , z 5 , and z 6  are as defined herein, and salts thereof. 
     The compounds of the invention are inhibitors of the ATF4 pathway and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with activated unfolded protein response pathways, such as Alzheimer&#39;s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington&#39;s disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting the ATF4 pathway and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

FIELD OF THE INVENTION

The present invention relates to substituted piperidine derivatives thatare inhibitors of the ATF4 pathway. The present invention also relatesto pharmaceutical compositions comprising such compounds and methods ofusing such compounds in the treatment of diseases/injuries associatedwith activated unfolded protein response pathways, such as cancer,pre-cancerous syndromes, Alzheimer's disease, spinal cord injury,traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinsondisease, Huntington's disease, Creutzfeldt-Jakob Disease, and relatedprion diseases, progressive supranuclear palsy, amyotrophic lateralsclerosis, myocardial infarction, cardiovascular disease, inflammation,fibrosis, chronic and acute diseases of the liver, chronic and acutediseases of the lung, chronic and acute diseases of the kidney, chronictraumatic encephalopathy (CTE), neurodegeneration, dementia, cognitiveimpairment, atherosclerosis, ocular diseases, arrhythmias, in organtransplantation and in the transportation of organs for transplantation.

BACKGROUND OF THE INVENTION

In metazoa, diverse stress signals converge at a single phosphorylationevent at serine 51 of a common effector, the translation initiationfactor eIF2α. This step is carried out by four eIF2α kinases inmammalian cells: PERK, which responds to an accumulation of unfoldedproteins in the endoplasmic reticulum (ER), GCN2 to amino acidstarvation and UV light, PKR to viral infection, and HRI to hemedeficiency. This collection of signaling pathways has been termed the“integrated stress response” (ISR), as they converge on the samemolecular event. eIF2α phosphorylation results in an attenuation oftranslation with consequences that allow cells to cope with the variedstresses (1).

eIF2 (which is comprised of three subunits, α, β, and γ) binds GTP andthe initiator Met-tRNA to form the ternary complex (eIF2-GTP-Met-tRNAi),which, in turn, associates with the 40S ribosomal subunit scanning the5′UTR ofmRNAs to select the initiating AUG codon. Upon phosphorylationof its a-subunit, eIF2 becomes a competitive inhibitor of itsGTP-exchange factor (GEF), eIF2B (2). The tight and nonproductivebinding of phosphorylated eIF2 to eIF2B prevents loading of the eIF2complex with GTP thus blocking ternary complex formation and reducingtranslation initiation (3). Because eIF2B is less abundant than eIF2,phosphorylation of only a small fraction of the total eIF2 has adramatic impact on eIF2B activity in cells.

Paradoxically, under conditions of reduced protein synthesis, a smallgroup of mRNAs that contain upstream open reading frames (uORFs) intheir 5′UTR are translationally up-regulated (4,5). These includemammalian ATF4 (a cAMP element binding (CREB) transcription factor) andCHOP (a pro-apoptotic transcription factor) (6-8). ATF4 regulates theexpression of many genes involved in metabolism and nutrient uptake andadditional transcription factors, such as CHOP, which is under bothtranslational and transcriptional control (9). Phosphorylation of eIF2αthus leads to preferential translation of key regulatory molecules anddirects diverse changes in the transcriptome of cells upon cellularstress.

One of the eIF2α kinases, PERK, lies at the intersection of the ISR andthe unfolded protein response (UPR) that maintains homeostasis ofprotein folding rates in the ER (10). The UPR is activated by unfoldedor misfolded proteins that accumulate in the ER lumen because of animbalance between protein folding load and protein folding capacity, acondition known as “ER stress”. In mammals, the UPR is comprised ofthree signaling branches mediated by ER-localized transmembrane sensors,PERK, IRE1, and ATF6. These sensor proteins detect the accumulation ofunfolded protein in the ER and transmit the information across the ERmembrane, initiating unique signaling pathways that converge in theactivation of an extensive transcriptional response, which ultimatelyresults in ER expansion (11). The lumenal stress-sensing domains of PERKand IRE1 are homologous and likely activated in analogous ways by directbinding to unfolded peptides (12). This binding event leads tooligomerization and trans-autophosphorylation of their cytosolic kinasedomains, and, for PERK, phosphorylation of its only known substrate,eIF2α. In this way, PERK activation results in a quick reduction in theload of newly synthesized proteins that are translocated into theER-lumen (13).

Upon ER stress, both the transcription factor XBP1s, produced as theconsequence of a non-conventional mRNA splicing reaction initiated byIRE1, and the transcription factor ATF6, produced by proteolysis andrelease from the ER membrane, collaborate with ATF4 to induce the vastUPR transcriptional response. Transcriptional targets of the UPR includethe ER protein folding machinery, the ER-associated degradationmachinery, and many other components functioning in the secretorypathway (14). Although the UPR initially mitigates ER stress and as suchconfers cytoprotection, persistent and severe ER stress leads toactivation of apoptosis that eliminates damaged cells (15,16).

Small-molecule therapeutics that inhibit the UPR and/or the IntegratedStress Response could be used in cancer as a single agent or incombination with other chemotherapeutics (17,18,19), for enhancement oflong-term memory (24,25), in neurodegenerative and prion associateddiseases (20), in white matter disease (VWM) (23) and in biotechnologyapplications that would benefit from increased protein translation.

It is an object of the instant invention to provide novel compounds thatprevent the translation of ATF4 or are inhibitors of the ATF4 pathway.

It is also an object of the present invention to provide pharmaceuticalcompositions that comprise a pharmaceutically acceptable excipient andcompounds of Formula (III).

It is also an object of the present invention to provide a method fortreating neurodegenerative diseases, cancer, and other diseases/injuriesassociated with activated unfolded protein response pathways such as:Alzheimer's disease, spinal cord injury, traumatic brain injury,ischemic stroke, stroke, diabetes, Parkinson disease, Huntington'sdisease, Creutzfeldt-Jakob Disease, and related prion diseases,amyotrophic lateral sclerosis, progressive supranuclear palsy,myocardial infarction, cardiovascular disease, inflammation, fibrosis,chronic and acute diseases of the liver, chronic and acute diseases ofthe lung, chronic and acute diseases of the kidney, chronic traumaticencephalopathy (CTE), neurodegeneration, dementias, atherosclerosis,ocular diseases, arrhythmias, in organ transplantation and in thetransportation of organs for transplantation that comprisesadministering novel inhibitors of the ATF4 pathway.

SUMMARY OF THE INVENTION

The invention is directed to substituted piperidine derivatives.Specifically, the invention is directed to compounds according toFormula III:

wherein A, B, X, Y, L¹, L², L³, R¹, R², R³, R⁴, R⁵, R⁶, R⁹, z², z⁴, z⁵,and z⁶ are as defined below; or a salt thereof including apharmaceutically acceptable salt thereof.

The present invention also relates to the discovery that the compoundsof Formula (III) are active as inhibitors of the ATF4 pathway.

The present invention also relates to the discovery that the compoundsof Formula (III) prevent the translation of ATF4.

This invention also relates to a method of treating Alzheimer's disease,which comprises administering to a subject in need thereof an effectiveamount of a compound of Formula (III) or a pharmaceutically acceptablesalt thereof.

This invention also relates to a method of treating Parkinson's disease,which comprises administering to a subject in need thereof an effectiveamount of a compound of Formula (III) or a pharmaceutically acceptablesalt thereof.

This invention also relates to a method of treating amyotrophic lateralsclerosis, which comprises administering to a subject in need thereof aneffective amount of a compound of Formula (III) or a pharmaceuticallyacceptable salt thereof.

This invention also relates to a method of treating Huntington'sdisease, which comprises administering to a subject in need thereof aneffective amount of a compound of Formula (III) or a pharmaceuticallyacceptable salt thereof.

This invention also relates to a method of treating Creutzfeldt-JakobDisease, which comprises administering to a subject in need thereof aneffective amount of a compound of Formula (III) or a pharmaceuticallyacceptable salt thereof.

This invention also relates to a method of treating progressivesupranuclear palsy (PSP), which comprises administering to a subject inneed thereof an effective amount of a compound of Formula (III) or apharmaceutically acceptable salt thereof.

This invention also relates to a method of treating dementia, whichcomprises administering to a subject in need thereof an effective amountof a compound of Formula (III) or a pharmaceutically acceptable saltthereof.

This invention also relates to a method of treating spinal cord injury,which comprises administering to a subject in need thereof an effectiveamount of a compound of Formula (III) or a pharmaceutically acceptablesalt thereof.

This invention also relates to a method of treating traumatic braininjury, which comprises administering to a subject in need thereof aneffective amount of a compound of Formula (III) or a pharmaceuticallyacceptable salt thereof.

This invention also relates to a method of treating ischemic stroke,which comprises administering to a subject in need thereof an effectiveamount of a compound of Formula (III) or a pharmaceutically acceptablesalt thereof.

This invention also relates to a method of treating diabetes, whichcomprises administering to a subject in need thereof an effective amountof a compound of Formula (III) or a pharmaceutically acceptable saltthereof.

This invention also relates to a method of treating a disease stateselected from myocardial infarction, cardiovascular disease,atherosclerosis, ocular diseases, and arrhythmias, which comprisesadministering to a subject in need thereof an effective amount of acompound of Formula (III) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating an integrated stressresponse-associated disease in a patient in need of such treatment, themethod including administering a therapeutically effective amount of acompound of Formula (III) or a pharmaceutically acceptable salt thereof,to the patient.

This invention also relates to a method of treating a disease associatedwith phosphorylation of eIF2α in a patient in need of such treatment,the method including administering a therapeutically effective amount ofa compound of Formula (III), or a pharmaceutically acceptable saltthereof, to the patient.

This invention also relates to a method of treating a disease in apatient in need of such treatment, the method including administering atherapeutically effective amount of a compound of Formula (III) or apharmaceutically acceptable salt thereof, to the patient, wherein thedisease is selected from the group consisting of cancer, aneurodegenerative disease, vanishing white matter disease, childhoodataxia with CNS hypomyelination, and an intellectual disabilitysyndrome.

This invention also relates to a method of improving long-term memory ina patient, the method including administering a therapeuticallyeffective amount of a compound of Formula (III) or a pharmaceuticallyacceptable salt thereof, to the patient.

This invention also relates to a method of increasing protein expressionof a cell or in vitro expression system, the method includingadministering an effective amount of a compound of Formula (III) or apharmaceutically acceptable salt thereof, to the cell or expressionsystem.

This invention also relates to a method of treating an inflammatorydisease in a patient in need of such treatment, the method includingadministering a therapeutically effective amount of a compound ofFormula (III), or a pharmaceutically acceptable salt thereof, to thepatient.

This invention also relates to a method of using the compounds ofFormula (III) in organ transplantation and in the transportation oforgans for transplantation.

Also included in the present invention are methods of co-administeringthe presently invented compounds with further active ingredients.

Included in the present invention is a method for treatingneurodegenerative diseases, cancer, and other diseases/injuriesassociated with activated unfolded protein response pathways such as:Alzheimer's disease, spinal cord injury, traumatic brain injury,ischemic stroke, stroke, diabetes, Parkinson disease, Huntington'sdisease, Creutzfeldt-Jakob Disease, and related prion diseases,amyotrophic lateral sclerosis, progressive supranuclear palsy,myocardial infarction, cardiovascular disease, inflammation, fibrosis,chronic and acute diseases of the liver, chronic and acute diseases ofthe lung, chronic and acute diseases of the kidney, chronic traumaticencephalopathy (CTE), neurodegeneration, dementias, atherosclerosis,ocular diseases, arrhythmias, in organ transplantation and in thetransportation of organs for transplantation that comprisesadministering the compounds of Formula (III).

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in therapy.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofAlzheimer's disease.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofParkinson's disease syndromes.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofamyotrophic lateral sclerosis.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofHuntington's disease.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofCreutzfeldt-Jakob Disease.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofprogressive supranuclear palsy (PSP).

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofdementia.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofspinal cord injury.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment oftraumatic brain injury.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofischemic stroke.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment ofdiabetes.

The invention also relates to a compound of Formula (III) or apharmaceutically acceptable salt thereof for use in the treatment of adisease state selected from: myocardial infarction, cardiovasculardisease, atherosclerosis, ocular diseases, and arrhythmias.

The invention also relates to the use of a compound of Formula (III) ora pharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of an integrated stress response-associateddisease.

The invention also relates to the use of a compound of Formula (III) ora pharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of a disease associated withphosphorylation of eIF2α.

The invention also relates to the use of a compound of Formula (III) ora pharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of a disease selected from the groupconsisting of: cancer, a neurodegenerative disease, vanishing whitematter disease, childhood ataxia with CNS hypomyelination, and anintellectual disability syndrome.

The invention also relates to the use of a compound of Formula (III) ora pharmaceutically acceptable salt thereof in the manufacture of amedicament for improving long-term memory.

The invention also relates to the use of a compound of Formula (III) ora pharmaceutically acceptable salt thereof in the manufacture of amedicament for increasing protein expression of a cell or in vitroexpression system.

The invention also relates to the use of a compound of Formula (III) ora pharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of inflammatory disease.

The invention also relates to the use of a compound of Formula (III) ora pharmaceutically acceptable salt thereof in the manufacture of amedicament in organ transplantation and in the transportation of organsfor transplantation.

The invention also relates to the use of a compound of Formula (III) ora pharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of a disease state selected from:neurodegenerative diseases, cancer, and other diseases/injuriesassociated with activated unfolded protein response pathways such as:Alzheimer's disease, spinal cord injury, traumatic brain injury,ischemic stroke, stroke, diabetes, Parkinson disease, Huntington'sdisease, Creutzfeldt-Jakob Disease, and related prion diseases,amyotrophic lateral sclerosis, progressive supranuclear palsy,myocardial infarction, cardiovascular disease, inflammation, fibrosis,chronic and acute diseases of the liver, chronic and acute diseases ofthe lung, chronic and acute diseases of the kidney, chronic traumaticencephalopathy (CTE), neurodegeneration, dementias, atherosclerosis,ocular diseases, arrhythmias, in organ transplantation and in thetransportation of organs for transplantation.

Included in the present invention are pharmaceutical compositions thatcomprise a pharmaceutical excipient and a compound of Formula (III) or apharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition as definedabove for use in therapy.

The invention also relates to a combination for use in therapy whichcomprises a therapeutically effective amount of (i) a compound ofFormula (III) or a pharmaceutically acceptable salt thereof; and (ii)further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

Included in the compounds of the invention and used in the methods ofthe invention are compounds of Formula (I):

wherein:

-   -   L² and L³ are independently a bond, —NH—, —O—, —S—, —S(O)—,        —S(O)₂—, substituted or unsubstituted C₁₋₆alkylene or        substituted or unsubstituted C₁₋₆heteroalkylene;    -   L¹ is selected from: a bond, —NH—, —C(R⁷)—, —O—, —S—, —S(O)—,        —S(O)₂—, substituted or unsubstituted C₁₋₆alkylene and        substituted or unsubstituted C₁₋₆heteroalkylene;    -   R¹ is CH—, or R¹ is C— and taken together with R³ and the        nitrogen to which R³ is attached, and optionally from 1 to 3        additional heteroatoms, to form a heterocycloalkyl, which is        optionally substituted with from 1 to 5 substituents        independently selected from:        -   fluoro, chloro, C₁₋₆alkyl, C₁₋₆alkyl substituted 1 to 6            times by fluoro, C₁₋₄alkoxy, C₁₋₄alkoxy substituted 1 to 6            times by fluoro, oxo, and —NH₂;    -   R³, R⁵ and R⁶ and are independently hydrogen, fluoro, chloro,        bromo, iodo, —OCH₃, —OCH₂Ph, —C(O)Ph, —CH₃, —CF₃, —CN, —S(O)CH₃,        —OH, —NH₂, —COOH, —CONH₂, —NO₂, —C(O)CH₃, —CH(CH₃)₂, —CCH,        —CH₂CCH, —SO₃H, —SO₂NH₂, —NHC(O)NH₂, —NHC(O)H, —NHOH, —OCF₃,        —OCHF₂, substituted or unsubstituted C₁₋₆alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   R² and R⁴ are independently NR⁸, O, or S;    -   R⁷ is selected from: ═NR⁸, ═O, and ═S;    -   R⁸ is selected from: hydrogen, C₁₋₆alkyl and C₁₋₆alkyl        substituted 1 to 6 times by fluoro;    -   z² and z⁴ are independently 0 or 1; and    -   z⁵ and z⁶ are independently an integer from 0 to 5;        and salts thereof.

This invention also relates to pharmaceutically acceptable salts of thecompounds of Formula (I).

Included in the compounds of the invention and used in the methods ofthe invention are compounds of Formula (II):

wherein:

-   -   L¹² and L¹³ are independently: —CH₂—O—, —O—CH₂—, —CH₂—CH₂—O—,        —O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—, and —O—CH₂—CH₂—CH₂—;    -   L¹¹ is selected from: a bond, —CH₂— and —C(O)—;    -   R¹¹ is CH— and R¹³ is hydrogen, or R¹¹ is C— and taken together        with R¹³ and the nitrogen to which R¹³ is attached form an        oxazolidine, which is optionally substituted by oxo;    -   R¹⁵ and R¹⁶ are independently hydrogen or chloro;    -   R¹² and R¹⁴ are O;    -   z¹² and z¹⁴ are independently 0 or 1; and    -   z¹⁵ and z¹⁶ are independently an integer from 0 to 5;        and salts thereof.

This invention also relates to pharmaceutically acceptable salts of thecompounds of Formula (II).

Included in the compounds of the invention and used in the methods ofthe invention are compounds of Formula (III):

wherein:

-   -   L² is selected from: a bond, —NH—, —O—, —S—, —S(O)—, —S(O)₂—,        substituted or unsubstituted C₁₋₆alkylene or substituted or        unsubstituted C₁₋₆heteroalkylene, or L² is further taken        together with B to form heterocycloalkyl;    -   L³ is selected from: a bond, —NH—, —O—, —S—, —S(O)—, —S(O)₂—,        substituted or unsubstituted C₁₋₆alkylene or substituted or        unsubstituted C₁₋₆heteroalkylene, or L³ is further taken        together with A to form heterocycloalkyl;    -   L¹ is selected from: a bond, —NH—, —C(R⁷)—, —O—, —S—, —S(O)—,        —S(O)₂—, substituted or unsubstituted C₁₋₆alkylene and        substituted or unsubstituted C₁₋₆heteroalkylene;    -   R¹ is CH—, or R¹ is C— and taken together with R³ and the        nitrogen to which R³ is attached, and optionally from 1 to 3        additional heteroatoms, to form a heterocycloalkyl, which is        optionally substituted with from 1 to 5 substituents        independently selected from:        -   fluoro, chloro, C₁₋₆alkyl, C₁₋₆alkyl substituted 1 to 6            times by fluoro, C₁₋₄alkoxy, C₁₋₄alkoxy substituted 1 to 6            times by fluoro, oxo, and —NH₂;    -   R³, R⁵ and R⁶ and are independently hydrogen, fluoro, chloro,        bromo, iodo, —OCH₃, —OCH₂Ph, —C(O)Ph, —CH₃, —CF₃, —CN, —S(O)CH₃,        —OH, —NH₂, —COOH, —CONH₂, —NO₂, —C(O)CH₃, —CH(CH₃)₂, —CCH,        —CH₂CCH, —SO₃H, —SO₂NH₂, —NHC(O)NH₂, —NHC(O)H, —NHOH, —OCF₃,        —OCHF₂, substituted or unsubstituted C₁₋₆alkylene, substituted        or unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl, provided R³ is absent when Z is a        nitrogen linked heteroaryl;    -   R² and R⁴ are independently NR⁸, O, or S;    -   R⁷ is selected from: ═NR⁸, ═O, and ═S;    -   R⁸ is selected from: hydrogen, C₁₋₆alkyl and C₁₋₆alkyl        substituted 1 to 6 times by fluoro;    -   R⁹ is selected from: hydrogen, fluoro, chloro, bromo, iodo, —OH,        C₁₋₃alkyl and C₁₋₃alkyl substituted with from 1 to 3        substituents independently selected from: fluoro, oxo, —OH, and        —NH₂;    -   A and B are independently aryl or heteroaryl;    -   z2 and z4 are independently 0 or 1;    -   z5 and z6 are independently an integer from 0 to 5;    -   X is absent or present as C₁₋₂alkyl or C₁₋₂alkyl substituted 1        to 2 times by fluoro, where the dotted lines represent optional        bonds of the alkyl chain of X;    -   Y is absent or present as C₁₋₂alkyl or C₁₋₂alkyl substituted 1        to 2 times by fluoro, where the dotted lines represent optional        bonds of the alkyl chain of Y; and    -   Z is nitrogen or a nitrogen linked heteroaryl;        and salts thereof.

This invention also relates to pharmaceutically acceptable salts of thecompounds of Formula (III).

Included in the compounds of the invention and used in the methods ofthe invention are compounds of Formula (IV):

wherein:

-   -   L¹² and L¹³ are independently: —CH₂—O—, —O—CH₂—, —CH₂—CH₂—O—,        —O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O— and —O—CH₂—CH₂—CH₂—;    -   L¹¹ is selected from: a bond, —CH₂— and —C(O)—;    -   R¹¹ is CH— and R¹³ is hydrogen, or R¹¹ is C— and taken together        with R¹³ and the nitrogen to which R¹³ is attached form an        oxazolidine, which is optionally substituted by oxo;    -   R¹⁵ and R¹⁶ are independently hydrogen or chloro;    -   R¹² and R¹⁴ are O;    -   R¹⁹ is selected from: hydrogen, fluoro, chloro, —OH, C₁₋₃alkyl        and C₁₋₃alkyl substituted with from 1 to 3 substituents        independently selected from: fluoro, oxo, and —OH;    -   z¹² and z¹⁴ are independently 0 or 1;    -   z¹⁵ and z¹⁶ are independently an integer from 0 to 5;    -   X¹ is absent or present as C₁₋₂alkyl or C₁₋₂alkyl substituted 1        to 2 times by fluoro, where the dotted lines represent optional        bonds of the alkyl chain of X; and    -   Y¹ is absent or present as C₁₋₂alkyl or C₁₋₂alkyl substituted 1        to 2 times by fluoro, where the dotted lines represent optional        bonds of the alkyl chain of Y; and salts thereof.

This invention also relates to pharmaceutically acceptable salts of thecompounds of Formula (IV).

Included in the compounds of the invention and used in the methods ofthe invention are compounds of Formula (V):

wherein:

-   -   L² is selected from: a bond, —NH—, —O—, —S—, —S(O)—, —S(O)₂—,        substituted or unsubstituted C₁₋₆alkylene or substituted or        unsubstituted C₁₋₆heteroalkylene, or L² is further taken        together with B to form heterocycloalkyl;    -   L³ is selected from: a bond, —NH—, —O—, —S—, —S(O)—, —S(O)₂—,        substituted or unsubstituted C₁₋₆alkylene or substituted or        unsubstituted C₁₋₆heteroalkylene, or L³ is further taken        together with A to form heterocycloalkyl;    -   L¹ is selected from: a bond, —NH—, —C(R⁷)—, —O—, —S—, —S(O)—,        —S(O)₂—, substituted or unsubstituted C₁₋₆alkylene and        substituted or unsubstituted C₁₋₆heteroalkylene;    -   R¹ is CH—, or R¹ is C— and taken together with R³ and the        nitrogen to which R³ is attached, and optionally from 1 to 3        additional heteroatoms, to form a heterocycloalkyl, which is        optionally substituted with from 1 to 5 substituents        independently selected from:        -   fluoro, chloro, C₁₋₆alkyl, C₁₋₆alkyl substituted 1 to 6            times by fluoro, C₁₋₄alkoxy, C₁₋₄alkoxy substituted 1 to 6            times by fluoro, oxo, and —NH₂;    -   R³, R⁵ and R⁶ and are independently hydrogen, fluoro, chloro,        bromo, iodo, —OCH₃, —OCH₂Ph, —C(O)Ph, —CH₃, —CF₃, —CN, —S(O)CH₃,        —OH, —NH₂, —COOH, —CONH₂, —NO₂, —C(O)CH₃, —CH(CH₃)₂, —CCH,        —CH₂CCH, —SO₃H, —SO₂NH₂, —NHC(O)NH₂, —NHC(O)H, —NHOH, —OCF₃,        —OCHF₂, substituted or unsubstituted C₁₋₆alkylene, substituted        or unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl, provided R³ is absent when Z is a        nitrogen linked heteroaryl;    -   R² and R⁴ are independently NR⁸, O, or S;    -   R⁷ is selected from: ═NR⁸, ═O, and ═S;    -   R⁸ is selected from: hydrogen, C₁₋₆alkyl and C₁₋₆alkyl        substituted 1 to 6 times by fluoro;    -   R⁹ is selected from: hydrogen, fluoro, chloro, bromo, iodo, —OH,        C₁₋₃alkyl and C₁₋₃alkyl substituted with from 1 to 3        substituents independently selected from: fluoro, oxo, —OH, and        —NH₂;    -   A and B are independently aryl or heteroaryl;    -   z2 and z4 are independently 0 or 1;    -   z5 and z6 are independently an integer from 0 to 5;    -   X is absent or present as C₁₋₂alkyl or C₁₋₂alkyl substituted 1        to 2 times by fluoro, where the dotted lines represent optional        bonds of the alkyl chain of X;    -   Y is absent or present as C₁₋₂alkyl or C₁₋₂alkyl substituted 1        to 2 times by fluoro, where the dotted lines represent optional        bonds of the alkyl chain of Y; and    -   Z is nitrogen or a nitrogen linked heteroaryl;        and salts thereof.

This invention also relates to pharmaceutically acceptable salts of thecompounds of Formula (V).

Included in the compounds of Formula (III) are:

-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-4-yl)acetamide;-   8-(2-(4-chlorophenoxy)acetyl)-3-(2-(4-chlorophenoxy)ethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;-   2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)acetamide;-   N-(2-(4-chlorophenoxy)ethyl)-1-(3-(4-chlorophenoxy)propanoyl)piperidine-4-carboxamide;-   2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propanoyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-((1-(2-(4-chlorophenoxy)acetyl)piperidin-4-yl)methyl)acetamide;-   N-(1-(2-((5-chloroisothiazol-3-yl)oxy)ethyl)piperidin-4-y)-2-(4-chlorophenoxy)acetamide;-   N-(1-(3-((5-chloroisothiazol-3-yl)oxy)propyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide;-   2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide;-   (R)-2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide;-   (S)-2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)pipe    rid in-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-fluoropropyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(2-(3-(4-chlorophenoxy)-2-hydroxypropyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-methoxypropyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(3-((6-chloropyridin-3-yl)oxy)propyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(2-(3-(4-chlorophenoxy)propyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide;-   N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-((5-chloropyridin-2-yl)oxy)acetamide;-   2-(4-chlorophenoxy)-N-(1-(3-((5-chloropyridin-2-yl)oxy)propyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(3-(3,4-dichlorophenoxy)propyl)piperidin-4-yl)acetamide;-   4-(2-((4-chlorophenoxy)methyl)-1H-imidazol-1-yl)-1-(3-(4-chlorophenoxy)propyl)piperidine;-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)-3-methylpiperidin-4-yl)acetamide;-   N-(4-chlorophenethyl)-1-(2-(4-chlorophenoxy)acetyl)piperidine-4-carboxamide;-   2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propanoyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(4-(4-chlorophenyl)butanoyl)-3-fluoropiperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)acetamide;-   2-(4-chlorophenoxy)-N-(2-(1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)ethyl)acetamide;-   N-((1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)methyl)-2-((6-chloropyridin-3-yl)oxy)acetamide;-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)-3-fluoropiperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(2-(2-(4-chlorophenoxy)acetyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-((1R,2R)-2-(4-chlorophenoxy)cyclopropane-1-carbonyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-((1R,2S)-2-(4-chlorophenoxy)cyclopropane-1-carbonyl)piperidin-4-yl)acetamide;-   N-(1-((1    S,2R)-2-(4-chlorobenzyl)cyclopropane-1-carbonyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide;-   N-(1-((1R,2R)-2-(4-chlorobenzyl)cyclopropane-1-carbonyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide;-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenyl)cyclopropane-1-carbonyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(4-(4-chlorophenyl)butanoyl)piperidin-4-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-methylpiperidin-4-yl)acetamide;-   N, 1-bis(2-(4-chlorophenoxy)ethyl)piperidine-4-carboxamide;-   N-(2-(4-chlorophenoxy)ethyl)-1-(3-(4-chlorophenoxy)propyl)piperidine-4-carboxamide;-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-hydroxypiperidin-4-yl)acetamide;-   6-chloro-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)chromane-2-carboxamide;-   N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-((6-chloropyridin-3-yl)oxy)acetamide;-   N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(3,4-dichlorophenoxy)acetamide;-   N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(2,4-dichlorophenoxy)acetamide;-   2-(4-chlorophenoxy)-N-((1R,5S)-8-(3-(4-chlorophenoxy)propyl)-8-azabicyclo[3.2.1]octan-3-yl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(2-(3,4-dichlorophenoxy)ethyl)-3-fluoropiperidin-4-yl)acetamide;-   N-(1-(2-(4-chlorophenoxy)ethyl)-3-fluoropiperidin-4-yl)-2-(3,4-dichlorophenoxy)acetamide;-   2-(4-chlorophenoxy)-N-((1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)methyl)acetamide;-   2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-fluoropiperidin-4-yl)acetamide;-   4-(4-chlorophenoxy)-2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)butanoic    acid;-   2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)-2-oxopiperidin-4-yl)acetamide;-   4-(4-chlorophenoxy)-2-(4-(2-(3,4-dichlorophenoxy)acetamido)piperidin-1-yl)butanoic    acid;-   2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)-4-(3,4-dichlorophenoxy)butanoic    acid;-   N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(4-(difluoromethoxy)phenoxy)acetamide;-   N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(4-cyclopropylphenoxy)acetamide;-   2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-N-methylacetamide;-   4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylic    acid; and-   4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylic    acid;-   and salts thereof including pharmaceutically acceptable salts    thereof.

L¹ may be a bond or substituted or unsubstituted C₁-C₆ alkylenealkylene. L¹ may be substituted or unsubstituted C₁-C₅ alkylene. L¹ maybe substituted or unsubstituted C₁-C₃ alkylene. L¹ may be substituted orunsubstituted methylene. L¹ may be a bond. L¹ may be an unsubstitutedalkylene. L¹ may be an unsubstituted methylene. L¹ may be anunsubstituted ethylene. L¹ may be a methylene substituted with anunsubstituted alkyl. L¹ may be a methylene substituted with anunsubstituted C₁-C₄ alkyl. L¹ may be a methylene substituted with anunsubstituted C₁-C₃ alkyl.

Suitably, R³ is hydrogen. Suitably, R³ is —CH₂CCH.

Suitably, R³ is substituted or unsubstituted C₁₋₆alkylene, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.Suitably, R³ is substituted or unsubstituted C₁₋₆alkylene. Suitably, R³is substituted or unsubstituted C₁-C₅ alkyl. Suitably, R³ is substitutedor unsubstituted C₁-C₄ alkyl. Suitably, R³ is substituted orunsubstituted C₁-C₃ alkyl. Suitably, R³ is unsubstituted C₁₋₆alkylene.Suitably, R³ is unsubstituted C₁-C₅ alkyl. Suitably, R³ is unsubstitutedC₁-C₄ alkyl. Suitably, R³ is unsubstituted C₁-C₃ alkyl. Suitably, R³ issubstituted or unsubstituted heteroalkyl. Suitably, R³ is substituted orunsubstituted 2 to 8 membered heteroalkyl. Suitably, R³ is unsubstituted2 to 8 membered heteroalkyl.

In embodiments, R⁵ is independently hydrogen, fluoro, chloro, bromo,iodo, —OCH₃, —OCH₂Ph, —C(O)Ph, —CH₃, —CF₃, —CN, —S(O)CH₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —C(O)CH₃, —CH(CH₃)₂, —CCH, —CH₂CCH, —SO₃H, —SO₂NH₂,—NHC(O)NH₂, —NHC(O)H, —NHOH, —OCH₃, —OCF₃, —OCHF₂, substituted orunsubstituted C₁₋₆alkylene, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R⁵ is independently hydrogen,fluoro, chloro, bromo, iodo, —OCH₃, —OCH₂Ph, —CH₃, —OH, —CF₃, —CN,—S(O)CH₃, —NO₂, —C(O)CH₃, —C(O)Ph, —CH(CH₃)₂, or —CCH. In embodiments,R⁵ is —F. In embodiments, R⁵ is —Cl. In embodiments, R⁵ is —Br. Inembodiments, R⁵ is —I. In embodiments, R⁵ is substituted orunsubstituted C₁₋₆alkylene, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R⁵ is unsubstitutedC₁₋₆alkylene, unsubstituted heteroalkyl, unsubstituted cycloalkyl,unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstitutedheteroaryl. In embodiments, R⁵ is —OCH₃. In embodiments, R⁵ is —OCH₂Ph.In embodiments, R⁵ is —CH₃. In embodiments, R⁵ is —OH. In embodiments,R⁵ is —CF₃. In embodiments, R⁵ is —CN. In embodiments, R⁵ is —S(O)CH₃.In embodiments, R⁵ is —NO₂. In embodiments, R⁵ is —C(O)CH₃. Inembodiments, R⁵ is —C(O)Ph. In embodiments, R⁵ is —CH(CH₃)₂. Inembodiments, R⁵ is —CCH. In embodiments, R⁵ is —CH₂CCH. In embodiments,R⁵ is —SO₃H. In embodiments, R⁵ is —SO₂NH₂. In embodiments, R⁵ is—NHC(O)NH₂. In embodiments, R⁵ is —NHC(O)H. In embodiments, R⁵ is —NHOH.In embodiments, R⁵ is-OCH₃. In embodiments, R is —OCF₃. In embodiments,R⁵ is —OCHF₂.

In embodiments, R⁶ is independently hydrogen, fluoro, chloro, bromo,iodo, —OCH₃, —OCH₂Ph, —C(O)Ph, —CH₃, —CF₃, —CN, —S(O)CH₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —C(O)CH₃, —CH(CH₃)₂, —CCH, —CH₂CCH, —SO₃H, —SO₂NH₂,—NHC(O)NH₂, —NHC(O)H, —NHOH, —OCH₃, —OCF₃, —OCHF₂, substituted orunsubstituted C₁₋₆alkylene, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R⁶ is independently hydrogen,fluoro, chloro, bromo, iodo, —OCH₃, —OCH₂Ph, —CH₃, —OH, —CF₃, —CN,—S(O)CH₃, —NO₂, —C(O)CH₃, —C(O)Ph, —CH(CH₃)₂, or —CCH. In embodiments,R⁶ is —F. In embodiments, R⁶ is —Cl.

In embodiments, R⁶ is —Br. In embodiments, R⁶ is —I. In embodiments, R⁶is substituted or unsubstituted C₁₋₆alkylene, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R⁶ is unsubstituted C₁₋₆alkylene, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R⁶ is—OCH₃. In embodiments, R⁶ is —OCH₂Ph. In embodiments, R⁶ is —CH₃. Inembodiments, R⁶ is —OH. In embodiments, R⁶ is —CF₃. In embodiments, R⁶is —CN. In embodiments, R⁶ is —S(O)CH₃. In embodiments, R⁶ is —NO₂. Inembodiments, R⁶ is —C(O)CH₃. In embodiments, R⁶ is —C(O)Ph. Inembodiments, R⁶ is —CH(CH₃)₂. In embodiments, R⁶ is —CCH. Inembodiments, R⁶ is —CH₂CCH. In embodiments, R⁶ is —SO₃H. In embodiments,R⁶ is —SO₂NH₂. In embodiments, R⁶ is —NHC(O)NH₂. In embodiments, R⁶ is—NHC(O)H. In embodiments, R⁶ is —NHOH. In embodiments, R⁶ is —OCH₃. Inembodiments, R⁶ is —OCF₃. In embodiments, R⁶ is —OCHF₂.

In embodiments, R² is NR⁸. In embodiments, R² is NH. In embodiments, R²is O. In embodiments, R² is S. In embodiments, R⁴ is NR⁸. Inembodiments, R⁴ is NH. In embodiments, R⁴ is O. In embodiments, R⁴ is S.In embodiments, R² and R⁴ are NH. In embodiments, R² and R⁴ are O. Inembodiments, R² and R⁴ are S. In embodiments, R² and R⁴ are NR⁸.

In embodiments, L² is a bond. In embodiments, L² is a substituted orunsubstituted C₁₋₆alkylene. In embodiments, L² is a substituted orunsubstituted C₁₋₆heteroalkylene. In embodiments, L² isL^(2A)-L^(2B)-L^(2C) and L^(2A) is bonded to the substituted orunsubstituted phenyl, which may be substituted with R⁵. L^(2A) is abond, —O—, —S—, —NH—, —S(O)—, or —S(O)₂—. L^(2B) is a bond orsubstituted or unsubstituted C₁₋₆alkylene. L^(2C) is a bond, —O—, or—NH—. In embodiments, L^(2A) is a bond. In embodiments, L^(2A) is —O—.In embodiments, L^(2A) is —S—. In embodiments, L^(2A) is —NH—. Inembodiments, L^(2A) is —S(O)—. In embodiments, L^(2A) is —S(O)₂—. Inembodiments, L^(2B) is a bond. In embodiments, L^(2B) is a substitutedor unsubstituted C₁₋₆alkylene. In embodiments, L^(2B) is anunsubstituted C₁₋₆alkylene. In embodiments, L^(2B) is a substituted orunsubstituted C₁-C₅ alkylene. In embodiments, L^(2B) is an unsubstitutedC₁-C₅ alkylene. In embodiments, L^(2B) is a substituted or unsubstitutedC₁-C₄ alkylene. In embodiments, L^(2B) is an unsubstituted C₁-C₄alkylene. In embodiments, L^(2B) is a substituted or unsubstituted C₁-C₃alkylene. In embodiments, L^(2B) is an unsubstituted C₁-C₃ alkylene. Inembodiments, L^(2B) is a substituted C₁-C₅ alkylene. In embodiments,L^(2B) is a substituted C₁-C₆ alkylene. In embodiments, L^(2B) is asubstituted C₁-C₅ alkylene. In embodiments, L^(2B) is a substitutedC₁-C₄ alkylene. In embodiments, L^(2B) is a C₁-C₆ alkylene substitutedwith —CF₃. In embodiments, L^(2C) is a bond. In embodiments, L^(2C) is—O—. In embodiments, L^(2C) is —NH—. In embodiments, L^(2A) is a bond;L^(2B) is unsubstituted methylene; and L^(2C) is —O—.

In embodiments, L³ is a bond. In embodiments, L³ is a substituted orunsubstituted C₁₋₆alkylene. In embodiments, L³ is a substituted orunsubstituted C₁₋₆heteroalkylene. In embodiments, L³ isL^(3A)-L^(3B)-L^(3C) and L^(3A) is bonded to the substituted orunsubstituted phenyl, which may be substituted with R⁵. L^(3A) is abond, —O—, —S—, —NH—, —S(O)—, or —S(O)₂—. L^(3B) is a bond orsubstituted or unsubstituted C₁₋₆alkylene. L^(3c) is a bond, —O—, or—NH—. In embodiments, L^(3A) is a bond. In embodiments, L^(3A) is —O—.In embodiments, L^(3A) is —S—. In embodiments, L^(3A) is —NH—. Inembodiments, L^(3A) is —S(O)—. In embodiments, L^(3A) is —S(O)₂—. Inembodiments, L^(3B) is a bond. In embodiments, L^(3B) is a substitutedor unsubstituted C₁₋₆alkylene. In embodiments, L^(3B) is anunsubstituted C₁₋₆alkylene. In embodiments, L^(3B) is a substituted orunsubstituted C₁-C₅ alkylene. In embodiments, L^(3B) is an unsubstitutedC₁-C₅ alkylene. In embodiments, L^(3B) is a substituted or unsubstitutedC₁-C₄ alkylene. In embodiments, L^(3B) is an unsubstituted C₁-C₄alkylene. In embodiments, L^(3B) is a substituted or unsubstitutedC₁-C₃alkylene. In embodiments, L^(3B) is an unsubstituted C₁-C₃alkylene. In embodiments, L^(3B) is a substituted C₁-C₅ alkylene. Inembodiments, L^(3B) is a substituted C₁-C₆ alkylene. In embodiments,L^(3B) is a substituted C₁-C₅ alkylene. In embodiments, L^(3B) is asubstituted C₁-C₄ alkylene. In embodiments, L^(3B) is a C₁-C₆ alkylenesubstituted with —CF₃. In embodiments, L^(3c) is a bond. In embodiments,L^(3c) is —O—. In embodiments, L^(3c) is —NH—. In embodiments, L^(3A) isa bond; L^(3B) is unsubstituted methylene; and L^(3c) is —O—.

In embodiments, the symbol z² is O. In embodiments, the symbol z² is 1.In embodiments, the symbol z⁴ is O. In embodiments, the symbol z⁴ is 1.In embodiments, the symbols z² and z⁴ are O. In embodiments, the symbolsz² and z⁴ are 1. In embodiments, the symbol z⁵ is O. In embodiments, thesymbol z⁵ is 1. In embodiments, the symbol z⁵ is 2. In embodiments, thesymbol z⁵ is 3. In embodiments, the symbol z⁵ is 4. In embodiments, thesymbol z⁶ is O. In embodiments, the symbol z⁶ is 1. In embodiments, thesymbol z⁶ is 2. In embodiments, the symbol z⁶ is 3. In embodiments, thesymbol z⁶ is 4.

The skilled artisan will appreciate that salts, includingpharmaceutically acceptable salts, of the compounds according to Formula(III) may be prepared. Indeed, in certain embodiments of the invention,salts including pharmaceutically-acceptable salts of the compoundsaccording to Formula (III) may be preferred over the respective free orunsalted compound. Accordingly, the invention is further directed tosalts, including pharmaceutically-acceptable salts, of the compoundsaccording to Formula (III).

The salts, including pharmaceutically acceptable salts, of the compoundsof the invention are readily prepared by those of skill in the art.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention.

Representative pharmaceutically acceptable acid addition salts include,but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate,bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate(camsylate), caprate (decanoate), caproate (hexanoate), caprylate(octanoate), cinnamate, citrate, cyclamate, digluconate,2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate(ethylenediaminetetraacetate), estolate (lauryl sulfate),ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate,fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate),glucoheptonate (gluceptate), gluconate, glucuronate, glutamate,glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate,hydrabamine (N,N′-di(dehydroabietyl)-ethylenediamine), hydrobromide,hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate,lactobionate, laurate, malate, maleate, malonate, mandelate,methanesulfonate (mesylate), methylsulfate, mucate,naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate(napsylate), nicotinate, nitrate, oleate, palmitate,p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate),pantothenate, pectinate, persulfate, phenylacetate,phenylethylbarbiturate, phosphate, polygalacturonate, propionate,p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate,sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate,tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide,undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include,but are not limited to, aluminium,2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine),arginine, benethamine (N-benzylphenethylamine), benzathine(N,N′-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth,calcium, chloroprocaine, choline, clemizole (1-pchlorobenzyl-2-pyrrolildine-1′-ylmethylbenzimidazole), cyclohexylamine,dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine,dimethylethanolamine, dopamine, ethanolamine, ethylenediamine,L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium,meglumine (N-methylglucamine), piperazine, piperidine, potassium,procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc.

The compounds according to Formula (III) may contain one or moreasymmetric centers (also referred to as a chiral center) and may,therefore, exist as individual enantiomers, diastereomers, or otherstereoisomeric forms, or as mixtures thereof. Chiral centers, such aschiral carbon atoms, may be present in a substituent such as an alkylgroup. Where the stereochemistry of a chiral center present in acompound of Formula (III), or in any chemical structure illustratedherein, if not specified the structure is intended to encompass allindividual stereoisomers and all mixtures thereof. Thus, compoundsaccording to Formula (III) containing one or more chiral centers may beused as racemic mixtures, enantiomerically or diastereomericallyenriched mixtures, or as enantiomerically or diastereomerically pureindividual stereoisomers.

The compounds according to Formula (III) and pharmaceutically acceptablesalts thereof may contain isotopically-labelled compounds, which areidentical to those recited in Formula (III) and following, but for thefact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of such isotopes include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine,iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 31P,32P, 35S, 18F, 36Cl, 123I and 125I.

Isotopically-labelled compounds, for example those into whichradioactive isotopes such as 3H or 14C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., 3H,and carbon-14, i.e., 14C, isotopes are particularly preferred for theirease of preparation and detectability. 11C and 18F isotopes areparticularly useful in PET (positron emission tomography), and 125Iisotopes are particularly useful in SPECT (single photon emissioncomputerized tomography), both are useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., 2H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds can generally be prepared bysubstituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds according to Formula (III) may also contain double bondsor other centers of geometric asymmetry. Where the stereochemistry of acenter of geometric asymmetry present in Formula (III), or in anychemical structure illustrated herein, is not specified, the structureis intended to encompass the trans (E) geometric isomer, the cis (Z)geometric isomer, and all mixtures thereof. Likewise, all tautomericforms are also included in Formula (III) whether such tautomers exist inequilibrium or predominately in one form.

The compounds of Formula (III) or salts, including pharmaceuticallyacceptable salts, thereof may exist in solid or liquid form. In thesolid state, the compounds of the invention may exist in crystalline ornoncrystalline form, or as a mixture thereof. For compounds of theinvention that are in crystalline form, the skilled artisan willappreciate that pharmaceutically acceptable solvates may be formedwherein solvent molecules are incorporated into the crystalline latticeduring crystallization. Solvates wherein water is the solvent that isincorporated into the crystalline lattice are typically referred to as“hydrates.” Hydrates include stoichiometric hydrates as well ascompositions containing vaiable amounts of water.

The skilled artisan will further appreciate that certain compounds ofFormula (III) or salts, including pharmaceutically acceptable saltsthereof that exist in crystalline form, including the various solvatesthereof, may exhibit polymorphism (i.e. the capacity to occur indifferent crystalline structures). These different crystalline forms aretypically known as “polymorphs.” Polymorphs have the same chemicalcomposition but differ in packing, geometrical arrangement, and otherdescriptive properties of the crystalline solid state.

Polymorphs, therefore, may have different physical properties such asshape, density, hardness, deformability, stability, and dissolutionproperties. Polymorphs typically exhibit different melting points, IRspectra, and X-ray powder diffraction patterns, which may be used foridentification. The skilled artisan will appreciate that differentpolymorphs may be produced, for example, by changing or adjusting thereaction conditions or reagents, used in making the compound. Forexample, changes in temperature, pressure, or solvent may result inpolymorphs. In addition, one polymorph may spontaneously convert toanother polymorph under certain conditions.

While aspects for each variable have generally been listed aboveseparately for each variable this invention includes those compounds inwhich several or each aspect in Formula (III) is selected from each ofthe aspects listed above. Therefore, this invention is intended toinclude all combinations of aspects for each variable.

Definitions

“Alkyl” and “alkylene”, and derivatives thereof, refer to a hydrocarbonchain having the specified number of “member atoms”. Alkyl beingmonovalent and alkylene being bivalent. For example, C₁-C₆ alkyl refersto an alkyl group having from 1 to 6 member atoms. Alkyl groups may besaturated, unsaturated, straight or branched. Representative branchedalkyl groups have one, two, or three branches. Alkyl and alkyleneincludes methyl, ethyl, ethylene, propyl (n-propyl and isopropyl),butene, butyl (n-butyl, isobutyl, and t-butyl), pentyl,methylcyclopropane, and hexyl.

In an embodiment, “alkyl” and “alkylene” further includes cycloalkyl inthe carbon chain, for example —CH₃cyclopropane-.

“Alkoxy” refers to an —O-alkyl group wherein “alkyl” is as definedherein. For example, C₁-C₄alkoxy refers to an alkoxy group having from 1to 4 member atoms. Representative branched alkoxy groups have one, two,or three branches. Examples of such groups include methoxy, ethoxy,propoxy, and butoxy.

“Aryl” refers to an aromatic hydrocarbon ring. Aryl groups aremonocyclic, bicyclic, and tricyclic ring systems having a total of fiveto fourteen ring member atoms, wherein at least one ring system isaromatic and wherein each ring in the system contains 3 to 7 memberatoms, such as phenyl, naphthalene, tetrahydronaphthalene and biphenyl.Suitably aryl is phenyl.

“Cycloalkyl”, unless otherwise defined, refers to a saturated orunsaturated non aromatic hydrocarbon ring having from three to sevencarbon atoms. Cycloalkyl groups are monocyclic ring systems. Forexample, C₃-C₇ cycloalkyl refers to a cycloalkyl group having from 3 to7 member atoms. Examples of cycloalkyl as used herein include:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl,cyclopentenyl, cyclohexenyl and cycloheptyl.

“Halo” refers to the halogen radicals fluoro, chloro, bromo, and iodo.

“Heteroaryl” refers to a monocyclic aromatic 4 to 8 member ringcontaining 1 to 7 carbon atoms and 1 to 4 heteroatoms, provided thatwhen the number of carbon atoms is 3, the aromatic ring contains atleast two heteroatoms, or to such aromatic ring fused to one or morerings, such as heteroaryl rings, aryl rings, heterocyclic rings,cycloalkyl rings. Heteroaryl groups containing more than one heteroatommay contain different heteroatoms. Heteroaryl includes but is notlimited to: benzoimidazolyl, benzothiazolyl, benzothiophenyl,benzopyrazinyl, benzotriazolyl, benzotriazinyl, benzo[1,4]dioxanyl,benzofuranyl, 9H-a-carbolinyl, cinnolinyl, furanyl, pyrazolyl,imidazolyl, indolizinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl,oxadiazolyl, phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl,phenazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrrolizinyl,pyrimidyl, isothiazolyl, furazanyl, pyrimidinyl, tetrazinyl, isoxazolyl,quinoxalinyl, quinazolinyl, quinolinyl, quinolizinyl, thienyl,thiophenyl, triazolyl, triazinyl, tetrazolopyrimidinyl,triazolopyrimidinyl, tetrazolyl, thiazolyl and thiazolidinyl. Suitablyheteroaryl is selected from: pyrazolyl, imidazolyl, oxazolyl andthienyl. Suitably heteroaryl is a pyridyl group or an imidazolyl group.Suitably heteroaryl is a pyridyl.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticring containing 4 to 12 member atoms, of which 1 to 11 are carbon atomsand from 1 to 6 are heteroatoms. Heterocycloalkyl groups containing morethan one heteroatom may contain different heteroatoms. Heterocycloalkylgroups are monocyclic ring systems or a monocyclic ring fused with anaryl ring or to a heteroaryl ring having from 3 to 6 member atoms.Heterocycloalkyl includes: pyrrolidinyl, tetrahydrofuranyl,dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, oxetanyl, thiazolidinyl,piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl,1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl,1,3-oxathianyl, 1,3-dithianyl, 1,3oxazolidin-2-one, hexahydro-1H-azepin,4,5,6,7,tetrahydro-1H-benzimidazol, piperidinyl,1,2,3,6-tetrahydro-pyridinyl and azetidinyl. Suitably,“heterocycloalkyl” includes: piperidine, tetrahydrofuran,tetrahydropyran and pyrrolidine.

“Heteroatom” refers to a nitrogen, sulphur or oxygen atom.

“Heteroalkyl” and “heteroalkylene” by itself or in combination withanother term, means, unless otherwise stated, a non-cyclic stablestraight or branched chain, or combinations thereof, including at leastone carbon atom and at least one heteroatom selected from the groupconsisting of O, N, P, Si, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. Heteroalkyl being monovalent andheteroalkylene being bivalent. The heteroalkyl and heteroalkylene groupsmay be taken together with another substituent to form aheterocycloalkyl group. The heteroatom(s) 0, N, P, S, and Si may beplaced at any interior position of the heteroalkyl or heteroalkylenegroup or at the position at which the alkyl group is attached to theremainder of the molecule. Examples include, but are not limited to:—CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)₂, —CH₂—S—CH₂—CH₃,—CH₂—CH₃, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, —CH═CHN(CH₃)₂, —O—CH₃, —O—CH₂—CH₃, and —CN. Examplesinclude, but are not limited to: —CH₃, —CH₂—, —CH₂—CH₂—O—CH₂—,CH₂—CH₂—NH—CH₂—, —CH₂—CH₂—N(CH₃)CH₂—, —CH₂—S—CH₂—CH₂—, —CH₂—CH₂—,—S(O)—CH₂—, —CH₂—CH₂—S(O)₂—CH₂—, —CH═CH—O—CH₂—, —Si(CH₃)₂CH₂—,—N(CH₃)CH₂—; —O—CH₂—CH₂—CH₂—. —CH₂—CH═N—OCH₂—, —CH═CHN(CH₃)CH₂—,—O—CH₂—, and —O—CH₂—CH₂—. Up to two or three heteroatoms may beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

“Substituted” as used herein, unless otherwise defined, is meant thatthe subject chemical moiety has from one to nine substituents, suitablyfrom one to five substituents, selected from the group consisting of:

-   -   fluoro,    -   chloro,    -   bromo,    -   iodo,    -   C₁₋₆alkyl,    -   C₁₋₆alkyl substituted with from 1 to 6 substituents        independently selected from: fluoro, oxo, —OH, —COOH, —NH₂, and        —CN,    -   —OC₁₋₆alkyl,    -   —OC₁₋₆alkyl substituted with from 1 to 6 substituents        independently selected from: fluoro, oxo, —OH, —COOH, —NH₂, and        —CN,    -   mercapto,    -   —SR^(X),        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   —S(O) R^(X)        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   —S(O)₂H,    -   —S(O)₂R^(X),        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   oxo,    -   hydroxy,    -   amino,    -   —NHR^(X),        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   NR^(x1)R^(x2),        -   where R^(x1) and R^(x2) are each independently selected from            C₁₋₆alkyl, and C₁₋₆alkyl substituted with from 1 to 6            substituents independently selected from: fluoro, oxo, —OH,            —COOH, —NH₂, and —CN,    -   guanidino,    -   —C(O)OH,    -   —C(O)OR^(X),        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   —C(O)NH₂,    -   —C(O)NHR^(X),        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   —C(O)NR^(x1)R^(x2),        -   where R^(x1) and R^(x2) are each independently selected from            C₁₋₆alkyl, and C₁₋₆alkyl substituted with from 1 to 6            substituents independently selected from: fluoro, oxo, —OH,            —COOH, —NH₂, and —CN,    -   —S(O)₂NH₂,    -   —S(O)₂NHR^(X),        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   —S(O)₂NR^(x1)R^(x2),        -   where R^(x1) and R^(x2) are each independently selected from            C₁₋₆alkyl, and C₁₋₆alkyl substituted with from 1 to 6            substituents independently selected from: fluoro, oxo, —OH,            —COOH, —NH₂, and —CN,    -   —NHS(O)₂H,    -   —NHS(O)₂R^(X),        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   —NHC(O)H,    -   —NHC(O)R^(X),        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   —NHC(O)NH₂,    -   —NHC(O)NHR^(X),        -   where R^(X) is selected from C₁₋₆alkyl, and C₁₋₆alkyl            substituted with from 1 to 6 substituents independently            selected from: fluoro, oxo, —OH, —COOH, —NH₂, and —CN,    -   —NHC(O)NR^(x1)R^(x2),        -   where R^(x1) and R^(x2) are each independently selected from            C₁₋₆alkyl, and C₁₋₆alkyl substituted with from 1 to 6            Substituents independently selected from: fluoro, oxo, —OH,            —COOH, —NH₂, and —CN, nitro, and cyano.

Suitably “substituted” means the subject chemical moiety has from one tofour substituents selected from the group consisting of:

-   -   fluoro,    -   chloro,    -   bromo,    -   iodo,    -   C₁₋₄alkyl,    -   C₁₋₄alkyl substituted with from 1 to 4 substituents        independently selected from: fluoro, oxo, —OH, —COOH, —NH₂, and        —CN,    -   —OC₁₋₄alkyl,    -   —OC₁₋₄alkyl substituted with from 1 to 4 substituents        independently selected from: fluoro, oxo, —OH, —COOH, —NH₂, and        —CN,    -   —SH,    -   S(O)₂H,    -   oxo,    -   hydroxy,    -   amino,    -   —NHR^(X),        -   where R^(X) is selected from C₁₋₄alkyl, and C₁₋₆alkyl            substituted one to 4 times by fluoro,    -   NR^(x1)R^(x2),        -   where R^(x1) and R^(x2) are each independently selected from            C₁₋₄alkyl, and C₁₋₄alkyl substituted one to four times by            fluoro,    -   guanidino,    -   —C(O)OH,    -   —C(O)OR^(X),        -   where R^(X) is selected from C₁₋₄alkyl, and C₁₋₄alkyl            substituted one to four times by fluoro,    -   —C(O)NH₂,    -   —C(O)NHR^(X),        -   where R^(X) is selected from C₁₋₄alkyl, and C₁₋₄alkyl            substituted one to four times by fluoro,    -   —C(O)NR^(x1)R^(x2),        -   where R^(x1) and R^(x2) are each independently selected from            C₁₋₄alkyl, and C₁₋₄alkyl substituted one to four times by            fluoro,    -   —S(O)₂NH₂,    -   —NHS(O)₂H,    -   —NHC(O)H,    -   —NHC(O)NH₂,    -   nitro, and    -   cyano.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

Ac (acetyl);Ac₂O (acetic anhydride);ACN (acetonitrile);AIBN (azobis(isobutyronitrile));BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl);BMS (borane—dimethyl sulphide complex);Bn (benzyl);Boc (tert-Butoxycarbonyl);Boc₂O (di-tert-butyl dicarbonate);BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate);CAN (cerric ammonium nitrate);Cbz (benzyloxycarbonyl);CSI (chlorosulfonyl isocyanate);CSF (cesium fluoride);DABCO (1,4-Diazabicyclo[2.2.2]octane);DAST (Diethylamino)sulfur trifluoride);DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene);

DCC (Dicyclohexyl Carbodiimide);

DCE (1,2-dichloroethane);DCM (dichloromethane);DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone);ATP (adenosine triphosphate);Bis-pinacolatodiboron(4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane);BSA (bovine serum albumin);C18 (refers to 18-carbon alkyl groups on silicon in HPLC stationaryphase);CH₃CN (acetonitrile);Cy (cyclohexyl);DCM (dichloromethane);DIPEA (Hünig's base, N-ethyl-N-(1-methylethyl)-2-propanamine);Dioxane (1,4-dioxane);DMAP (4-dimethylaminopyridine);DME (1,2-dimethoxyethane);DMEDA (N,N′-dimethylethylenediamine);

DMF (N,N-dimethylformamide);

DMSO (dimethylsulfoxide);DPPA (diphenyl phosphoryl azide);EDC (N-(3-dimethylaminopropyl)-N′ethylcarbodiimide);EDTA (ethylenediaminetetraacetic acid);EtOAc (ethyl acetate);EtOH (ethanol);Et₂O (diethyl ether);HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);HATU (O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate);HOAt (1-hydroxy-7-azabenzotriazole);HOBt (1-hydroxybenzotriazole);HOAc (acetic acid);HPLC (high pressure liquid chromatography);HMDS (hexamethyldisilazide);

Hunig's Base (N,N-Diisopropylethylamine);

IPA (isopropyl alcohol);Indoline (2,3-dihydro-1H-indole);KHMDS (potassium hexamethyldisilazide);LAH (lithium aluminum hydride);LDA (lithium diisopropylamide);LHMDS (lithium hexamethyldisilazide);MeOH (methanol);MTBE (methyl tert-butyl ether);mCPBA (m-chloroperbezoic acid);NaHMDS (sodium hexamethyldisilazide);

NBS (N-bromosuccinimide);

PE (petroleum ether);Pd₂(dba)₃ (Tris(dibenzylideneacetone)dipalladium(0);Pd(dppf)Cl₂.DCM Complex([1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethanecomplex);PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate);PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate);RPHPLC (reverse phase high pressure liquid chromatography);RT (room temperature);Sat. (saturated);SFC (supercritical fluid chromatography);SGC (silica gel chromatography);SM (starting material);TLC (thin layer chromatography);TEA (triethylamine);TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl, free radical);TFA (trifluoroacetic acid); andTHF (tetrahydrofuran).All references to ether are to diethyl ether and brine refers to asaturated aqueous solution of NaCl.

Methods of Use

The compounds according to Formula (III) and pharmaceutically acceptablesalts thereof are inhibitors of the ATF4 pathway. Compounds which areinhibitors of the ATF4 pathway are readily identified by exhibitingactivity in the ATF4 Cell Based Assay below. These compounds arepotentially useful in the treatment of conditions wherein the underlyingpathology is attributable to (but not limited to) modulation of theeIF2alpha pathway, for example, neurodegenerative disorders, cancer,cardiovascular and metabolic diseases. Accordingly, in another aspectthe invention is directed to methods of treating such conditions.

The Integrated Stress Response (ISR) is a collection of cellular stressresponse pathways that converge in phosphorylation of the translationinitiation factor eIF2α resulting in a reduction in overall translationin cells. Mammalian cells have four eIF2α kinases that phosphorylatethis initiation factor in the same residue (serine 51); PERK isactivated by the accumulation of unfolded proteins in the endoplasmicreticulum (ER), GCN2 is activated by amino acid starvation, PKR by viralinfection and HRI by heme deficiency. Activation of these kinasesdecreases bulk protein synthesis but it also culminates in increasedexpression of specific mRNAs that contain uORFs. Two examples of thesemRNAs are the transcription factor ATF4 and the pro-apoptotic gene CHOP.Phosphorylation of eIF2α upon stress and the concomitant reduction inprotein translation has been shown to both have cytoprotective andcytotoxic effects depending on the cellular context and duration andseverity of the stress. An integrated stress response-associated diseaseis a disease characterized by increased activity in the integratedstress response (e.g. increased phosphorylation of eIF2α by an eIF2αkinase compared to a control such as a subject without the disease). Adisease associated with phosphorylation of eIF2α is diseasecharacterized by an increase in phosphorylation of eIF2α relative to acontrol, such as a subject without the disease.

Activation of PERK occurs upon ER stress and hypoxic conditions and itsactivation and effect on translation has been shown to be cytoprotectivefor tumor cells [17]. Adaptation to hypoxia in the tumormicroenvironment is critical for survival and metastatic potential. PERKhas also been shown to promote cancer proliferation by limitingoxidative DNA damage and death [18, 19]. Moreover, a newly identifiedPERK inhibitor has been shown to have antitumor activity in a humanpancreatic tumor xenograft model [20]. Compounds disclosed hereindecrease the viability of cells that are subjected to ER-stress. Thus,pharmacological and acute inhibition of the PERK branch with thecompounds disclosed herein results in reduced cellular fitness. Duringtumor growth, compounds disclosed herein, that block the cytoprotectiveeffects of eIF2α phosphorylation upon stress may prove to be potentanti-proliferative agents.

It is known that under certain stress conditions several eIF2α kinasescan be simultaneously activated. For example, during tumor growth, thelack of nutrients and hypoxic conditions are known to both activate GCN2and PERK. Like PERK, GCN2 and their common target, ATF4, have beenproposed to play a cytoprotective role [21]. By blocking signaling byboth kinases, compounds disclosed herein may bypass the ability of theISR to protect cancer cells against the effects of low nutrients andoxygen levels encountered during the growth of the tumor.

Prolonged ER stress leads to the accumulation of CHOP, a pro-apoptoticmolecule. In a prion mouse model, overexpression of the phosphatase ofeIF2α increased survival of prion-infected mice whereas sustained eIF2αphosphorylation decreased survival [22]. The restoration of proteintranslation rates during prion disease was shown to rescue synapticdeficits and neuronal loss. The compounds disclosed herein that makecells insensitive to eIF2α phosphorylation sustain protein translation.Compounds disclosed herein could prove potent inhibitors of neuronalcell death in prion disease by blocking the deleterious effects ofprolonged eIF2α phosphorylation. Given the prevalence of proteinmisfolding and activation on the UPR in several neurodegenerativediseases (e.g. Alzheimer's (AD) and Parkinson's (PD)), manipulation ofthe PERK-eIF2α branch could prevent synaptic failure and neuronal deathacross the spectrum of these disorders.

Another example of tissue-specific pathology that is linked toheightened eIF2α phosphorylation is the fatal brain disorder, vanishingwhite matter disease (VWM) or childhood ataxia with CNS hypo-myelination(CACH). This disease has been linked to mutation in eIF2B, the GTPexchange factor that is necessary for eIF2 function in translation [23].eIF2α phosphorylation inhibits the activity of eIF2B and mutations inthis exchange factor that reduce its exchange activity exacerbate theeffects of eIF2α phosphorylation. The severe consequences of the CACHmutations point to the dangers of UPR hyper-activation, especially as itpertains to the myelin-producing oligodendrocyte. Small molecules, suchas compounds disclosed herein, that block signaling through eIF2αphosphorylation may reduce the deleterious effects of itshyper-activation in VWM.

In another aspect is provided a method of improving long-term memory ina patient, the method including administering a therapeuticallyeffective amount of a compound of Formula (III) to the patient. Inembodiments, the patient is human. In embodiments, the patient is amammal.

In embodiments, the compounds set forth herein are provided aspharmaceutical compositions including the compound and apharmaceutically acceptable excipient. In embodiments of the method, thecompound, or a pharmaceutically acceptable salt thereof, isco-adminstered with a second agent (e.g. therapeutic agent). Inembodiments of the method, the compound, or a pharmaceuticallyacceptable salt thereof, is co-adminstered with a second agent (e.g.therapeutic agent), which is administered in a therapeutically effectiveamount. In embodiments, the second agent is an agent for improvingmemory.

Induction of long-term memory (LTM) has been shown to be facilitated bydecreased and impaired by increased eIF2α phosphorylation. The datastrongly support the notion that under physiological conditions, adecrease in eIF2α phosphorylation constitutes a critical step for thelong term synaptic changes required for memory formation and ATF4 hasbeen shown to be an important regulator of these processes [24][25][26]. It is not known what the contributions of the different eIF2αkinases to learning is or whether each play a differential role in thedifferent parts of the brain. Regardless of the eIF2α kinase/sresponsible for phosphorylation of eIF2α in the brain, compoundsdisclosed herein that block translation and ATF4 production make themideal molecules to block the effects of this phosphorylation event onmemory. Pharmacological treatment with compounds disclosed hereinincrease spatial memory and enhance auditory and contextual fearconditioning.

Regulators of translation, such as the compounds of Formula (III), couldserve as therapeutic agents that improve memory in human disordersassociated with memory loss such as Alzheimer's disease and in otherneurological disorders that activate the UPR in neurons and thus couldhave negative effects on memory consolidation such as Parkinson'sdisease, Amyotrophic lateral sclerosis and prion diseases. In addition,a mutation in eIF2γ, that disrupts complex integrity linked intellectualdisability (intellectual disability syndrome or ID) to impairedtranslation initiation in humans [27]. Hence, two diseases with impairedeIF2 function, ID and VWM, display distinct phenotypes but both affectmainly the brain and impair learning.

The compounds of Formula (III) are also useful in applications whereincreasing protein production output is desirable, such as in vitro cellfree systems for protein production. In vitro systems have basal levelsof eIF2α phosphorylation that reduce translational output [28, 29].Similarly production of antibodies by hybridomas may also be improved byaddition of compounds disclosed herein.

In another aspect is provided a method of increasing protein expressionof a cell or in vitro expression system, the method includingadministering an effective amount of a compound of Formula (III) to thecell or expression system. In embodiments, the method is a method ofincreasing protein expression by a cell and includes administering aneffective amount of a compound of Formula (III) to the cell. Inembodiments, the method is a method of increasing protein expression byan in vitro protein expression system and includes administering aneffective amount of a compound of Formula (III) to the in vitro (e.g.cell free) protein expression system.

In embodiments, the compounds set forth herein are provided aspharmaceutical compositions including the compound and apharmaceutically acceptable excipient. In embodiments of the method, thecompound, or a pharmaceutically acceptable salt thereof, isco-adminstered with a second agent. In embodiments of the method, thecompound, or a pharmaceutically acceptable salt thereof, isco-adminstered with a second agent, which is administered in atherapeutically effective amount. In embodiments, the second agent is anagent for improving protein expression.

Suitably, the present invention relates to a method for treating orlessening the severity of breast cancer, including inflammatory breastcancer, ductal carcinoma, and lobular carcinoma.

Suitably the present invention relates to a method for treating orlessening the severity of colon cancer.

Suitably the present invention relates to a method for treating orlessening the severity of pancreatic cancer, including insulinomas,adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinarcell carcinoma, and glucagonoma.

Suitably the present invention relates to a method for treating orlessening the severity of skin cancer, including melanoma, includingmetastatic melanoma.

Suitably the present invention relates to a method for treating orlessening the severity of lung cancer including small cell lung cancer,non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, andlarge cell carcinoma.

Suitably the present invention relates to a method for treating orlessening the severity of cancers selected from the group consisting ofbrain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme,Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease,Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,medulloblastoma, head and neck, kidney, liver, melanoma, ovarian,pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamouscarcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate,sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblasticT cell leukemia, chronic myelogenous leukemia, chronic lymphocyticleukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acutemyelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblasticT cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantlecell leukemia, multiple myeloma, megakaryoblastic leukemia, multiplemyeloma, acute megakaryocytic leukemia, promyelocytic leukemia,erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkinslymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicularlymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvalcancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor), neuroendocrine cancers and testicularcancer.

Suitably the present invention relates to a method for treating orlessening the severity of pre-cancerous syndromes in a mammal, includinga human, wherein the pre-cancerous syndrome is selected from: cervicalintraepithelial neoplasia, monoclonal gammapathy of unknown significance(MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions,skin nevi (pre-melanoma), prostatic intraepithleial (intraductal)neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps andsevere hepatitis or cirrhosis.

Suitably the present invention relates to a method for treating orlessening the severity of neurodegenerative diseases/injury, such asAlzheimer's disease, spinal cord injury, traumatic brain injury,ischemic stroke, stroke, diabetes, Parkinson disease, Huntington'sdisease, Creutzfeldt-Jakob Disease, and related prion diseases,progressive supranuclear palsy, amyotrophic lateral sclerosis,myocardial infarction, cardiovascular disease, inflammation, fibrosis,chronic and acute diseases of the liver, chronic and acute diseases ofthe lung, chronic and acute diseases of the kidney, chronic traumaticencephalopathy (CTE), neurodegeneration, dementia, cognitive impairment,atherosclerosis, ocular diseases, arrhythmias, in organ transplantationand in the transportation of organs for transplantation.

Suitably the present invention relates to a method for preventing organdamage during and after organ transplantation and in the transportationof organs for transplantation. The method of preventing organ damageduring and after organ transplantation will comprise the in vivoadministration of a compound of Formula (III). The method of preventingorgan damage during the transportation of organs for transplantationwill comprise adding a compound of Formula (III) to the solution housingthe organ during transportation.

Suitably the present invention relates to a method for treating orlessening the severity of ocular diseases/angiogenesis. The method oftreating or lessening the severity of ocular diseases/angiogenesis willcomprise the in vivo administration of a compound of Formula (III). Inembodiments of methods according to the invention, the disorder ofocular diseases, including vascular leakage can be: edema orneovascularization for any occlusive or inflammatory retinal vasculardisease, such as rubeosis irides, neovascular glaucoma, pterygium,vascularized glaucoma filtering blebs, conjunctival papilloma; choroidalneovascularization, such as neovascular age-related macular degeneration(AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema, suchas post surgical macular edema, macular edema secondary to uveitisincluding retinal and/or choroidal inflammation, macular edema secondaryto diabetes, and macular edema secondary to retinovascular occlusivedisease (i.e. branch and central retinal vein occlusion); retinalneovascularization due to diabetes, such as retinal vein occlusion,uveitis, ocular ischemic syndrome from carotid artery disease,ophthalmic or retinal artery occlusion, sickle cell retinopathy, otherischemic or occlusive neovascular retinopathies, retinopathy ofprematurity, or Eale's Disease; and genetic disorders, such asVonHippel-Lindau syndrome.

In some embodiments, the neovascular age-related macular degeneration iswet age-related macular degeneration. In other embodiments, theneovascular age-related macular degeneration is dry age-related maculardegeneration and the patient is characterized as being at increased riskof developing wet age-related macular degeneration.

The methods of treatment of the invention comprise administering aneffective amount of a compound according to Formula (III) or apharmaceutically acceptable salt, thereof to a patient in need thereof.

The invention also provides a compound according to Formula (III) or apharmaceutically-acceptable salt thereof for use in medical therapy, andparticularly in therapy for: cancer, pre-cancerous syndromes,Alzheimer's disease, spinal cord injury, traumatic brain injury,ischemic stroke, stroke, diabetes, Parkinson disease, Huntington'sdisease, Creutzfeldt-Jakob Disease, and related prion diseases,progressive supranuclear palsy, amyotrophic lateral sclerosis,myocardial infarction, cardiovascular disease, inflammation, fibrosis,chronic and acute diseases of the liver, chronic and acute diseases ofthe lung, chronic and acute diseases of the kidney, chronic traumaticencephalopathy (CTE), neurodegeneration, dementia, cognitive impairment,atherosclerosis, ocular diseases, in organ transplantation andarrhythmias. The invention also provides a compound according to Formula(II) or a pharmaceutically-acceptable salt thereof for use in preventingorgan damage during the transportation of organs for transplantation.Thus, in further aspect, the invention is directed to the use of acompound according to Formula (III) or a pharmaceutically acceptablesalt thereof in the preparation of a medicament for the treatment of adisorder characterized by activation of the UPR, such as cancer.

The methods of treatment of the invention comprise administering a safeand effective amount of a compound of Formula (III), or apharmaceutically acceptable salt thereof to a mammal, suitably a human,in need thereof.

As used herein, “treating”, and derivatives thereof, in reference to acondition means: (1) to ameliorate or prevent the condition or one ormore of the biological manifestations of the condition, (2) to interferewith (a) one or more points in the biological cascade that leads to oris responsible for the condition or (b) one or more of the biologicalmanifestations of the condition, (3) to alleviate one or more of thesymptoms or effects associated with the condition, or (4) to slow theprogression of the condition or one or more of the biologicalmanifestations of the condition.

The term “treating” and derivatives thereof refers to therapeutictherapy. Therapeutic therapy is appropriate to alleviate symptions or totreat at early signs of disease or its progression. Prophylactic therapyis appropriate when a subject has, for example, a strong family historyof neurodegenerative diseases. Prophylactic therapy is appropriate whena subject has, for example, a strong family history of cancer or isotherwise considered at high risk for developing cancer, or when asubject has been exposed to a carcinogen.

The skilled artisan will appreciate that “prevention” is not an absoluteterm. In medicine, “prevention” is understood to refer to theprophylactic administration of a drug to substantially diminish thelikelihood or severity of a condition or biological manifestationthereof, or to delay the onset of such condition or biologicalmanifestation thereof.

As used herein, “safe and effective amount” in reference to a compoundof Formula (III), or a pharmaceutically acceptable salt thereof, meansan amount of the compound sufficient to treat the patient's conditionbut low enough to avoid serious side effects (at a reasonablebenefit/risk ratio) within the scope of sound medical judgment. A safeand effective amount of the compound will vary with the particular routeof administration chosen; the condition being treated; the severity ofthe condition being treated; the age, size, weight, and physicalcondition of the patient being treated; the medical history of thepatient to be treated; the duration of the treatment; the nature ofconcurrent therapy; the desired therapeutic effect; and like factors,but can nevertheless be routinely determined by the skilled artisan.

As used herein, “patient”, and derivatives thereof refers to a human orother mammal, suitably a human.

The compounds of Formula (III) or pharmaceutically acceptable saltsthereof may be administered by any suitable route of administration,including systemic administration. Systemic administration includes oraladministration, and parenteral administration. Parenteral administrationrefers to routes of administration other than enteral, transdermal, orby inhalation, and is typically by injection or infusion. Parenteraladministration includes intravenous, intramuscular, and subcutaneousinjection or infusion.

The compounds of Formula (III) or pharmaceutically acceptable saltsthereof may be administered once or according to a dosing regimenwherein a number of doses are administered at varying intervals of timefor a given period of time. For example, doses may be administered one,two, three, or four times per day. Doses may be administered until thedesired therapeutic effect is achieved or indefinitely to maintain thedesired therapeutic effect. Suitable dosing regimens for a compound ofthe invention depend on the pharmacokinetic properties of that compound,such as absorption, distribution, and half-life, which can be determinedby the skilled artisan. In addition, suitable dosing regimens, includingthe duration such regimens are administered, for a compound of theinvention depend on the condition being treated, the severity of thecondition being treated, the age and physical condition of the patientbeing treated, the medical history of the patient to be treated, thenature of concurrent therapy, the desired therapeutic effect, and likefactors within the knowledge and expertise of the skilled artisan. Itwill be further understood by such skilled artisans that suitable dosingregimens may require adjustment given an individual patient's responseto the dosing regimen or over time as individual patient needs change.

Additionally, the compounds of Formula (III) orpharmaceutically-acceptable salts thereof may be administered asprodrugs. As used herein, a “prodrug” of a compound of the invention isa functional derivative of the compound which, upon administration to apatient, eventually liberates the compound of the invention in vivo.Administration of a compound of the invention as a prodrug may enablethe skilled artisan to do one or more of the following: (a) modify theonset of the compound in vivo; (b) modify the duration of action of thecompound in vivo; (c) modify the transportation or distribution of thecompound in vivo; (d) modify the solubility of the compound in vivo; and(e) overcome a side effect or other difficulty encountered with thecompound. Where a —COOH or —OH group is present, pharmaceuticallyacceptable esters can be employed, for example methyl, ethyl, and thelike for —COOH, and acetate maleate and the like for —OH, and thoseesters known in the art for modifying solubility or hydrolysischaracteristics.

The compounds of Formula (III) and pharmaceutically acceptable saltsthereof may be co-administered with at least one other active agentknown to be useful in the treatment of cancer or pre-canceroussyndromes.

By the term “co-administration” as used herein is meant eithersimultaneous administration or any manner of separate sequentialadministration of an ATF4 pathway inhibiting compound, as describedherein, and a further active agent or agents, known to be useful in thetreatment of cancer, including chemotherapy and radiation treatment. Theterm further active agent or agents, as used herein, includes anycompound or therapeutic agent known to or that demonstrates advantageousproperties when administered to a patient in need of treatment forcancer. Preferably, if the administration is not simultaneous, thecompounds are administered in a close time proximity to each other.Furthermore, it does not matter if the compounds are administered in thesame dosage form, e.g. one compound may be administered by injection andanother compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus asusceptible tumor being treated may be co-administered in the treatmentof cancer in the present invention. Examples of such agents can be foundin Cancer Principles and Practice of Oncology by V. T. Devita and S.Hellman (editors), 6^(th) edition (Feb. 15, 2001), Lippincott Williams &Wilkins Publishers. A person of ordinary skill in the art would be ableto discern which combinations of agents would be useful based on theparticular characteristics of the drugs and the cancer involved. Typicalanti-neoplastic agents useful in the present invention include, but arenot limited to, anti-microtubule agents such as diterpenoids and vincaalkaloids; platinum coordination complexes; alkylating agents such asnitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, andtriazenes; antibiotic agents such as anthracyclins, actinomycins andbleomycins; topoisomerase II inhibitors such as epipodophyllotoxins;antimetabolites such as purine and pyrimidine analogues and anti-folatecompounds; topoisomerase I inhibitors such as camptothecins; hormonesand hormonal analogues; signal transduction pathway inhibitors;non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeuticagents; proapoptotic agents; cell cycle signaling inhibitors; proteasomeinhibitors; and inhibitors of cancer metabolism.

Examples of a further active ingredient or ingredients (anti-neoplasticagent) for use in combination or co-administered with the presentlyinvented ATF4 pathway inhibiting compounds are chemotherapeutic agents.

Suitably, the pharmaceutically active compounds of the invention areused in combination with a VEGFR inhibitor, suitably5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide,or a pharmaceutically acceptable salt, suitably the monohydrochloridesalt thereof, which is disclosed and claimed in in InternationalApplication No. PCT/US01/49367, having an International filing date ofDec. 19, 2001, International Publication Number WO02/059110 and anInternational Publication date of Aug. 1, 2002, the entire disclosure ofwhich is hereby incorporated by reference, and which is the compound ofExample 69.5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamidecan be prepared as described in International Application No.PCT/US01/49367.

In one embodiment, the cancer treatment method of the claimed inventionincludes the co-administration a compound of Formula (III) and/or apharmaceutically acceptable salt thereof and at least oneanti-neoplastic agent, such as one selected from the group consisting ofanti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormonal analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents,cell cycle signaling inhibitors; proteasome inhibitors; and inhibitorsof cancer metabolism.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

Additionally, the compounds described herein can be co-administered withconventional immunotherapeutic agents including, but not limited to,immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.).

In a further embodiment, the compounds described herein can beco-administered with conventional radiotherapeutic agents including, butnot limited to, radionuclides such as ⁴⁷Sc, ⁶⁴C ⁶⁷C, ⁸⁹Sr, ⁸⁶Y, ⁸⁷Y, and²¹²Bi, optionally conjugated to antibodies directed against tumorantigens.

Additional examples of a further active ingredient or ingredients(anti-neoplastic agent) for use in combination or co-administered withthe presently invented ATF4 pathway inhibiting compounds are anti-PD-L1agents.

Anti-PD-L1 antibodies and methods of making the same are known in theart.

Such antibodies to PD-L1 may be polyclonal or monoclonal, and/orrecombinant, and/or humanized.

Exemplary PD-L1 antibodies are disclosed in:

-   -   U.S. Pat. No. 8,217,149; Ser. No. 12/633,339;    -   U.S. Pat. No. 8,383,796; Ser. No. 13/091,936;    -   U.S. Pat. No. 8,552,154; Ser. No. 13/120,406;    -   US patent publication No. 20110280877; 13/068337;    -   US Patent Publication No. 20130309250; 13/892671;    -   WO2013019906;    -   WO2013079174;    -   U.S. application Ser. No. 13/511,538 (filed Aug. 7, 2012), which        is the US National Phase of International Application No.        PCT/US10/58007 (filed 2010);    -   and    -   U.S. application Ser. No. 13/478,511 (filed May 23, 2012).

Additional exemplary antibodies to PD-L1 (also referred to as CD274 orB7-H1) and methods for use are disclosed in U.S. Pat. No. 7,943,743;US20130034559, WO2014055897, U.S. Pat. Nos. 8,168,179; and 7,595,048.PD-L1 antibodies are in development as immuno-modulatory agents for thetreatment of cancer.

In one embodiment, the antibody to PD-L1 is an antibody disclosed inU.S. Pat. No. 8,217,149. In another embodiment, the anti-PD-L1 antibodycomprises the CDRs of an antibody disclosed in U.S. Pat. No. 8,217,149.

In another embodiment, the antibody to PD-L1 is an antibody disclosed inU.S. application Ser. No. 13/511,538. In another embodiment, theanti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S.application Ser. No. 13/511,538.

In another embodiment, the antibody to PD-L1 is an antibody disclosed inapplication Ser. No. 13/478,511. In another embodiment, the anti-PD-L1antibody comprises the CDRs of an antibody disclosed in U.S. applicationSer. No. 13/478,511.

In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1105). Inanother embodiment, the anti-PD-L1 antibody is MPDL3280A (RG7446). Inanother embodiment, the anti-PD-L1 antibody is MED14736.

Additional examples of a further active ingredient or ingredients(anti-neoplastic agent) for use in combination or co-administered withthe presently invented ATF4 pathway inhibiting compounds are PD-1antagonist.

“PD-1 antagonist” means any chemical compound or biological moleculethat blocks binding of PD-L1 expressed on a cancer cell to PD-1expressed on an immune cell (T cell, B cell or NKT cell) and preferablyalso blocks binding of PD-L2 expressed on a cancer cell to theimmune-cell expressed PD-1. Alternative names or synonyms for PD-1 andits ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1,PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC,Btdc and CD273 for PD-L2. In any embodiments of the aspects orembodiments of the present invention in which a human individual is tobe treated, the PD-1 antagonist blocks binding of human PD-L1 to humanPD-1, and preferably blocks binding of both human PD-L1 and PD-L2 tohuman PD-1. Human PD-1 amino acid sequences can be found in NCBI LocusNo.: NP 005009. Human PD-L1 and PD-L2 amino acid sequences can be foundin NCBI Locus No.: NP_054862 and NP_079515, respectively.

PD-1 antagonists useful in the any of the aspects of the presentinvention include a monoclonal antibody (mAb), or antigen bindingfragment thereof, which specifically binds to PD-1 or PD-L1, andpreferably specifically binds to human PD-1 or human PD-L1. The mAb maybe a human antibody, a humanized antibody or a chimeric antibody, andmay include a human constant region. In some embodiments, the humanconstant region is selected from the group consisting of IgG1, IgG2,IgG3 and IgG4 constant regions, and in preferred embodiments, the humanconstant region is an IgG1 or IgG4 constant region. In some embodiments,the antigen binding fragment is selected from the group consisting ofFab, Fab′-SH, F(ab′)₂, scFv and Fv fragments.

Examples of mAbs that bind to human PD-1, and useful in the variousaspects and embodiments of the present invention, are described in U.S.Pat. Nos. 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,168,757,WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358.

Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in any ofthe aspects and embodiments of the present invention include: MK-3475, ahumanized IgG4 mAb with the structure described in WHO Drug Information,Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy andlight chain amino acid sequences shown in FIG. 6; nivolumab, a humanIgG4 mAb with the structure described in WHO Drug Information, Vol. 27,No. 1, pages 68-69 (2013) and which comprises the heavy and light chainamino acid sequences shown in FIG. 7; the humanized antibodies h409A11,h409A16 and h409A17, which are described in WO2008/156712, and AMP-514,which is being developed by Medimmune.

Other PD-1 antagonists useful in the any of the aspects and embodimentsof the present invention include an immunoadhesin that specificallybinds to PD-1, and preferably specifically binds to human PD-1, e.g., afusion protein containing the extracellular or PD-1 binding portion ofPD-L1 or PD-L2 fused to a constant region such as an Fc region of animmunoglobulin molecule. Examples of immunoadhesion molecules thatspecifically bind to PD-1 are described in WO2010/027827 andWO2011/066342. Specific fusion proteins useful as the PD-1 antagonist inthe treatment method, medicaments and uses of the present inventioninclude AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusionprotein and binds to human PD-1.

Other examples of mAbs that bind to human PD-L1, and useful in thetreatment method, medicaments and uses of the present invention, aredescribed in WO2013/019906, WO2010/077634 A1 and U.S. Pat. No.8,383,796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonistin the treatment method, medicaments and uses of the present inventioninclude MPDL3280A, BMS-936559, MED14736, MSB0010718C.

KEYTRUDA/pembrolizumab is an anti-PD-1 antibody marketed for thetreatment of lung cancer by Merck. The amino acid sequence ofpembrolizumab and methods of using are disclosed in U.S. Pat. No.8,168,757.

Opdivo/nivolumab is a fully human monoclonal antibody marketed byBristol Myers Squibb directed against the negative immunoregulatoryhuman cell surface receptor PD-1 (programmed death-1 or programmed celldeath-1/PCD-1) with immunopotentiation activity. Nivolumab binds to andblocks the activation of PD-1, an Ig superfamily transmembrane protein,by its ligands PD-L1 and PD-L2, resulting in the activation of T-cellsand cell-mediated immune responses against tumor cells or pathogens.Activated PD-1 negatively regulates T-cell activation and effectorfunction through the suppression of P13k/Akt pathway activation. Othernames for nivolumab include: BMS-936558, MDX-1106, and ONO-4538. Theamino acid sequence for nivolumab and methods of using and making aredisclosed in U.S. Pat. No. 8,008,449.

Additional examples of a further active ingredient or ingredients(anti-neoplastic agent) for use in combination or co-administered withthe presently invented ATF4 pathway inhibiting compounds areimmuno-modulators.

As used herein “immuno-modulators” refer to any substance includingmonoclonal antibodies that affects the immune system. The ICOS bindingproteins of the present invention can be considered immune-modulators.Immuno-modulators can be used as anti-neoplastic agents for thetreatment of cancer. For example, immune-modulators include, but are notlimited to, anti-CTLA-4 antibodies such as ipilimumab (YERVOY) andanti-PD-1 antibodies (Opdivo/nivolumab and Keytruda/pembrolizumab).Other immuno-modulators include, but are not limited to, OX-40antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BBantibodies and GITR antibodies.

Yervoy (ipilimumab) is a fully human CTLA-4 antibody marketed by BristolMyers Squibb. The protein structure of ipilimumab and methods are usingare described in U.S. Pat. Nos. 6,984,720 and 7,605,238.

Suitably, the compounds of the invention are combined with an inhibitorof the activity of the protein kinase R (PKR)-like ER kinase, PERK.

Suitably, the compounds of Formula (III) and pharmaceutically acceptablesalts thereof may be co-administered with at least one other activeagent known to be useful in the treatment of neurodegenerativediseases/injury.

Suitably, the compounds of Formula (III) and pharmaceutically acceptablesalts thereof may be co-administered with at least one other activeagent known to be useful in the treatment of diabetes.

Suitably, the compounds of Formula (III) and pharmaceutically acceptablesalts thereof may be co-administered with at least one other activeagent known to be useful in the treatment of cardiovascular disease.

Suitably, the compounds of Formula (III) and pharmaceutically acceptablesalts thereof may be co-administered with at least one other activeagent known to be useful in the treatment of ocular diseases.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating cancer(e.g. pancreatic cancer, breast cancer, multiple myeloma, or cancers ofsecretory cells), neurodegenerative diseases, vanishing white matterdisease, childhood ataxia with CNS hypo-myelination, and/or intellectualdisability syndromes (e.g. associated with impaired function of eIF2 orcomponents in a signal transduction pathway including eIF2), or withadjunctive agents that may not be effective alone, but may contribute tothe efficacy of the active agent.

In embodiments, the compounds set forth herein are provided aspharmaceutical compositions including the compound and apharmaceutically acceptable excipient. In embodiments of the method, thecompound, or a pharmaceutically acceptable salt thereof, isco-adminstered with a second agent (e.g. therapeutic agent). Inembodiments of the method, the compound, or a pharmaceuticallyacceptable salt thereof, is co-adminstered with a second agent (e.g.therapeutic agent), which is administered in a therapeutically effectiveamount. In embodiments of the method, the second agent is an agent fortreating cancer (e.g. pancreatic cancer, breast cancer, multiplemyeloma, or cancers of secretory cells), neurodegenerative diseases,vanishing white matter disease, childhood ataxia with CNShypo-myelination, and/or intellectual disability syndromes (e.g.associated with impaired function of eIF2 or components in a signaltransduction pathway including eIF2), or an inflammatory disease (e.g.POCD or TBI). In embodiments, the second agent is an anti-cancer agent.In embodiments, the second agent is a chemotherapeutic. In embodiments,the second agent is an agent for improving memory. In embodiments, thesecond agent is an agent for treating a neurodegenerative disease. Inembodiments, the second agent is an agent for treating vanishing whitematter disease. In embodiments, the second agent is an agent fortreating childhood ataxia with CNS hypo-myelination. In embodiments, thesecond agent is an agent for treating an intellectual disabilitysyndrome. In embodiments, the second agent is an agent for treatingpancreatic cancer. In embodiments, the second agent is an agent fortreating breast cancer. In embodiments, the second agent is an agent fortreating multiple myeloma. In embodiments, the second agent is an agentfor treating myeloma. In embodiments, the second agent is an agent fortreating a cancer of a secretory cell. In embodiments, the second agentis an agent for reducing eIF2α phosphorylation. In embodiments, thesecond agent is an agent for inhibiting a pathway activated by eIF2αphosphorylation. In embodiments, the second agent is an agent forinhibiting the integrated stress response. In embodiments, the secondagent is an anti-inflammatory agent.

The term “eIF2alpha” or “eIF2α” refers to the protein “Eukaryotictranslation initiation factor 2A”. In embodiments, “eIF2alpha” or“eIF2α” refers to the human protein. Included in the term “eIF2alpha” or“eIF2α” are the wildtype and mutant forms of the protein. Inembodiments, “eIF2alpha” or “eIF2α” refers to the protein associatedwith Entrez Gene 83939, OMIM 609234, UniProt Q9BY44, and/or RefSeq(protein) NP 114414.

Suitably, the present invention relates to a method for treating anintegrated stress response associated disease in a patient in need ofsuch treatment, the method including administering a therapeuticallyeffective amount of a compound of Formula (III), or a pharmaceuticallyacceptable salt thereof, to the patient.

Suitably, the integrated stress response-associated disease is cancer.Suitably, the integrated stress response-associated disease is aneurodegenerative disease. Suitably, the integrated stressresponse-associated disease is vanishing white matter disease.

Suitably, the integrated stress response-associated disease is childhoodataxia with CNS hypo-myelination. Suitably, the integrated stressresponse-associated disease is an intellectual disability syndrome.

Suitably, the present invention relates to a method for treating adisease associated with phosphorylation of eIF2α in a patient in need ofsuch treatment, the method including administering a therapeuticallyeffective amount of a compound of Formula (III), or a pharmaceuticallyacceptable salt thereof, to the patient.

Suitably, the disease associated with phosphorylation of eIF2 α iscancer. Suitably, the disease associated with phosphorylation of eIF2 αis a neurodegenerative disease.

Suitably, the disease associated with phosphorylation of eIF2 α isvanishing white matter disease. Suitably, the disease associated withphosphorylation of eIF2 α is childhood ataxia with CNS hypo-myelination.Suitably, the disease associated with phosphorylation of eIF2 α is anintellectual disability syndrome.

Suitably, the present invention relates to a method for treating adisease selected from the group consisting of cancer, aneurodegenerative disease, vanishing white matter disease, childhoodataxia with CNS hypomyelination, and an intellectual disabilitysyndrome.

Suitably, the present invention relates to a method for treating aninflammatory disease in a patient in need of such treatment, the methodincluding administering a therapeutically effective amount of a compoundof Formula (III), or a pharmaceutically acceptable salt thereof, to thepatient.

Suitably, the inflammatory disease is associated with neurologicalinflammation. Suitably, the inflammatory disease is postoperativecognitive dysfunction. Suitably, the inflammatory disease is traumaticbrain injury or chronic traumatic encephalopathy (CTE).

In embodiments of the method of treating a disease, the disease isselected from the group consisting of cancer, a neurodegenerativedisease, vanishing white matter disease, childhood ataxia with CNShypo-myelination, and an intellectual disability syndrome. Inembodiments of the method of treating a disease, the disease is cancer.

In embodiments of the method of treating a disease, the disease is aneurodegenerative disease. In embodiments of the method of treating adisease, the disease is vanishing white matter disease. In embodimentsof the method of treating a disease, the disease is childhood ataxiawith CNS hypo-myelination. In embodiments of the method of treating adisease, the disease is an intellectual disability syndrome. Inembodiments of the method of treating a disease, the disease isassociated with phosphorylation of eIF2α. In embodiments of the methodof treating a disease, the disease is associated with an eIF2α signalingpathway. In embodiments of the method of treating a disease, the diseaseis a cancer of a secretory cell type. In embodiments of the method oftreating a disease, the disease is pancreatic cancer. In embodiments ofthe method of treating a disease, the disease is breast cancer. Inembodiments of the method of treating a disease, the disease is multiplemyeloma. In embodiments of the method of treating a disease, the diseaseis lymphoma. In embodiments of the method of treating a disease, thedisease is leukemia. In embodiments of the method of treating a disease,the disease is a hematopoietic cell cancer.

In embodiments of the method of treating a disease, the disease isAlzheimer's disease. In embodiments of the method of treating a disease,the disease is Amyotrophic lateral sclerosis. In embodiments of themethod of treating a disease, the disease is Creutzfeldt-Jakob disease.In embodiments of the method of treating a disease, the disease isfrontotemporal dementia. In embodiments of the method of treating adisease, the disease is Gerstmann-Straussler-Scheinker syndrome. Inembodiments of the method of treating a disease, the disease isHuntington's disease. In embodiments of the method of treating adisease, the disease is HIV-associated dementia. In embodiments of themethod of treating a disease, the disease is kuru. In embodiments of themethod of treating a disease, the disease is Lewy body dementia. Inembodiments of the method of treating a disease, the disease is Multiplesclerosis. In embodiments of the method of treating a disease, thedisease is Parkinson's disease. In embodiments of the method of treatinga disease, the disease is a Prion disease.

In embodiments of the method of treating a disease, the disease is aninflammatory disease. In embodiments, the inflammatory disease ispostoperative cognitive dysfunction. In embodiments, the inflammatorydisease is traumatic brain injury. In embodiments, the inflammatorydisease is arthritis. In embodiments, the inflammatory disease isrheumatoid arthritis. In embodiments, the inflammatory disease ispsoriatic arthritis. In embodiments, the inflammatory disease isjuvenile idiopathic arthritis. In embodiments, the inflammatory diseaseis multiple sclerosis. In embodiments, the inflammatory disease issystemic lupus erythematosus (SLE). In embodiments, the inflammatorydisease is myasthenia gravis. In embodiments, the inflammatory diseaseis juvenile onset diabetes. In embodiments, the inflammatory disease isdiabetes mellitus type 1. In embodiments, the inflammatory disease isGuillain-Barre syndrome. In embodiments, the inflammatory disease isHashimoto's encephalitis. In embodiments, the inflammatory disease isHashimoto's thyroiditis. In embodiments, the inflammatory disease isankylosing spondylitis. In embodiments, the inflammatory disease ispsoriasis. In embodiments, the inflammatory disease is Sjogren'ssyndrome. In embodiments, the inflammatory disease is vasculitis. Inembodiments, the inflammatory disease is glomerulonephritis. Inembodiments, the inflammatory disease is auto-immune thyroiditis. Inembodiments, the inflammatory disease is Behcet's disease. Inembodiments, the inflammatory disease is Crohn's disease. Inembodiments, the inflammatory disease is ulcerative colitis. Inembodiments, the inflammatory disease is bullous pemphigoid. Inembodiments, the inflammatory disease is sarcoidosis. In embodiments,the inflammatory disease is ichthyosis. In embodiments, the inflammatorydisease is Graves ophthalmopathy. In embodiments, the inflammatorydisease is inflammatory bowel disease. In embodiments, the inflammatorydisease is Addison's disease. In embodiments, the inflammatory diseaseis Vitiligo. In embodiments, the inflammatory disease is asthma. Inembodiments, the inflammatory disease is allergic asthma. Inembodiments, the inflammatory disease is acne vulgaris. In embodiments,the inflammatory disease is celiac disease. In embodiments, theinflammatory disease is chronic prostatitis. In embodiments, theinflammatory disease is inflammatory bowel disease. In embodiments, theinflammatory disease is pelvic inflammatory disease. In embodiments, theinflammatory disease is reperfusion injury. In embodiments, theinflammatory disease is sarcoidosis. In embodiments, the inflammatorydisease is transplant rejection. In embodiments, the inflammatorydisease is interstitial cystitis. In embodiments, the inflammatorydisease is atherosclerosis. In embodiments, the inflammatory disease isatopic dermatitis.

In embodiments, the method of treatment is a method of prevention. Forexample, a method of treating postsurgical cognitive dysfunction mayinclude preventing postsurgical cognitive dysfunction or a symptom ofpostsurgical cognitive dysfunction or reducing the severity of a symptomof postsurgical cognitive dysfunction by administering a compounddescribed herein prior to surgery.

In an embodiment, this invention provides a compound of Formula (III),or a pharmaceutically acceptable salt thereof, for use in the treatmentof a disease selected from the group consisting of cancer, aneurodegenerative disease, vanishing white matter disease, childhoodataxia with CNS hypomyelination, and an intellectual disabilitysyndrome.

In an embodiment, this invention provides a compound of Formula (III),or a pharmaceutically acceptable salt thereof, for use in the treatmentof an integrated stress response associated disease.

In an embodiment, this invention provides a compound of Formula (III),or a pharmaceutically acceptable salt thereof, for use in the treatmentof a disease associated with phosphorylation of eIF2α.

In an embodiment, this invention provides for the use of a compound ofFormula (III), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a disease selected fromthe group consisting of cancer, a neurodegenerative disease, vanishingwhite matter disease, childhood ataxia with CNS hypomyelination, and anintellectual disability syndrome.

In an embodiment, this invention provides for the use of a compound ofFormula (III), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment an integrated stressresponse associated disease.

In an embodiment, this invention provides for the use of a compound ofFormula (III), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a disease associatedwith phosphorylation of eIF2α.

Compositions

The pharmaceutically active compounds within the scope of this inventionare useful as ATF4 pathway inhibitors in mammals, particularly humans,in need thereof.

The present invention therefore provides a method of treating cancer,neurodegeneration and other conditions requiring ATF4 pathwayinhibition, which comprises administering an effective amount of acompound of Formula (III) or a pharmaceutically acceptable salt thereof.The compounds of Formula (III) also provide for a method of treating theabove indicated disease states because of their demonstrated ability toact as ATF4 pathway inhibitors. The drug may be administered to apatient in need thereof by any conventional route of administration,including, but not limited to, intravenous, intramuscular, oral,topical, subcutaneous, intradermal, intraocular and parenteral.Suitably, a ATF4 pathway inhibitor may be delivered directly to thebrain by intrathecal or intraventricular route, or implanted at anappropriate anatomical location within a device or pump thatcontinuously releases the ATF4 pathway inhibiting drug.

The pharmaceutically active compounds of the present invention areincorporated into convenient dosage forms such as capsules, tablets, orinjectable preparations. Solid or liquid pharmaceutical carriers areemployed. Solid carriers include, starch, lactose, calcium sulfatedihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, and stearic acid. Liquid carriers include syrup,peanut oil, olive oil, saline, and water. Similarly, the carrier ordiluent may include any prolonged release material, such as glycerylmonostearate or glyceryl distearate, alone or with a wax. The amount ofsolid carrier varies widely but, preferably, will be from about 25 mg toabout 1 g per dosage unit. When a liquid carrier is used, thepreparation will be in the form of a syrup, elixir, emulsion, softgelatin capsule, sterile injectable liquid such as an ampoule, or anaqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are made following conventionaltechniques of a pharmaceutical chemist involving mixing, granulating,and compressing, when necessary, for tablet forms, or mixing, fillingand dissolving the ingredients, as appropriate, to give the desired oralor parenteral products.

Doses of the presently invented pharmaceutically active compounds in apharmaceutical dosage unit as described above will be an efficacious,nontoxic quantity preferably selected from the range of 0.001-100 mg/kgof active compound, preferably 0.001-50 mg/kg. When treating a humanpatient in need of a ATF4 pathway inhibitor, the selected dose isadministered preferably from 1-6 times daily, orally or parenterally.Preferred forms of parenteral administration include topically,rectally, transdermally, by injection and continuously by infusion. Oraldosage units for human administration preferably contain from 0.05 to3500 mg of active compound. Oral administration, which uses lowerdosages, is preferred. Parenteral administration, at high dosages,however, also can be used when safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular ATF4 pathwayinhibitor in use, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Additionalfactors depending on the particular patient being treated will result ina need to adjust dosages, including patient age, weight, diet, and timeof administration.

When administered to prevent organ damage in the transportation oforgans for transplantation, a compound of Formula (III) is added to thesolution housing the organ during transportation, suitably in a bufferedsolution.

The method of this invention of inducing ATF4 pathway inhibitoryactivity in mammals, including humans, comprises administering to asubject in need of such activity an effective ATF4 pathway inhibitingamount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (III)or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use as a ATF4 pathway inhibitor.

The invention also provides for the use of a compound of Formula (III)or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use in therapy.

The invention also provides for the use of a compound of Formula (III)or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use in treating cancer, pre-cancerous syndromes,Alzheimer's disease, spinal cord injury, traumatic brain injury,ischemic stroke, stroke, diabetes, Parkinson disease, Huntington'sdisease, Creutzfeldt-Jakob Disease, and related prion diseases,progressive supranuclear palsy, amyotrophic lateral sclerosis,myocardial infarction, cardiovascular disease, inflammation, fibrosis,chronic and acute diseases of the liver, chronic and acute diseases ofthe lung, chronic and acute diseases of the kidney, chronic traumaticencephalopathy (CTE), neurodegeneration, dementia, cognitive impairment,atherosclerosis, ocular diseases, arrhythmias, in organ transplantationand in the transportation of organs for transplantation.

The invention also provides for the use of a compound of Formula (III)or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use in preventing organ damage during the transportationof organs for transplantation.

The invention also provides for a pharmaceutical composition for use asa ATF4 pathway inhibitor which comprises a compound of Formula (III) ora pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

The invention also provides for a pharmaceutical composition for use inthe treatment of cancer which comprises a compound of Formula (III) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

In addition, the pharmaceutically active compounds of the presentinvention can be co-administered with further active ingredients, suchas other compounds known to treat cancer, or compounds known to haveutility when used in combination with a ATF4 pathway inhibitor.

The invention also provides novel processes and novel intermeditesuseful in preparing the presently invented compounds.

The invention also provides a pharmaceutical composition comprising from0.5 to 1,000 mg of a compound of Formula (I) or pharmaceuticallyacceptable salt thereof and from 0.5 to 1,000 mg of a pharmaceuticallyacceptable excipient.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following Examples are, therefore, to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way.

EXAMPLES

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

Example 12-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-4-yl)acetamide

Step 1:

To a solution of 4-chlorophenol (15 g, 116.67 mmol, 1 equiv) in DMF (100mL) at room temperature was added anhydrous potassium carbonate (24.15g, 175.01 mmol, 1.5 equiv) portionwise. After stirring for 2 minutes,methyl-2-bromoacetate (13.3 mL, 140.01 mmol, 1.2 equiv) was added. Thereaction mixture was heated at 80° C. for 4 h. After consumption of thestarting material (TLC, 5% EtOAc in hexane), the reaction mixture wascooled to room temperature, diluted with water (100 mL) and extractedwith EtOAc (2×100 mL). The combined organic layer was washed with brinesolution (50 mL), dried over anhydrous sodium sulphate, filtered andconcentrated en vacuo to give the crude product. The crude product waspurified by flash column chromatography (Combiflash) using a silica gelcolumn and the product was eluted at 15% ethyl acetate in hexane.Fractions containing product were concentrated to give methyl2-(4-chlorophenoxy)acetate (22.5 g, 96.5% yield) as pale yellow liquid.¹H NMR (400 MHz, CDCl₃): δ ppm 3.67 (s, 3H), 4.78 (s, 2H), 6.91-6.95 (m,2H), 7.28-7.32 (m, 2H).

Step 2:

To a solution of methyl 2-(4-chlorophenoxy)acetate (22.5 g, 112.15 mmol,1 equiv) in ethanol (100 mL) at 0° C. was added a solution of sodiumhydroxide (5.38 g, 134.58 mmol) in water (10 mL). After stirring for 5minutes at 0° C., the reaction mixture was allowed to warm to roomtemperature and then refluxed for 2.5 h during which the startingmaterial was completely consumed. Heating was removed and the reactionmixture was allowed to cool down to room temperature. Ethanol wasevaporated removed en vacuo and the reaction mixture was diluted withwater (50 mL) followed by extraction with Et₂O (50 mL). The aqueouslayer was acidified with 1 N HCl up to pH 3 and the precipitated productwas filtered through a cintered funnel, washed with ice-cold water (10mL) and dried under high vacuum to give 2-(4-chlorophenoxy)acetic acid(20 g, 95.6% yield) as white solid. LCMS (ES) m/z=186.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 4.65 (s, 2H), 6.91 (d, J=9.2 Hz, 2H), 7.29 (d,J=8.8 Hz, 2H), 12.98 (bs, 1H).

Step 3:

To a solution of piperidin-4-amine (0.075 g, 0.74 mmol, 1 equiv) in DCM(7.0 mL) at 0° C. was added triethylamine (0.52 mL, 3.74 mmol, 5 equiv)and 2-(4-chlorophenoxy)acetic acid (0.3 g, 1.64 mmol, 2.2 equiv). Afterstirring for 5 minutes, T₃P (50 wt. % in ethyl acetate) (2.84 mL, 4.48mmol, 6 equiv) was added to the reaction mixture. Then reaction mixturewas allowed to stir at room temperature for 16 h. After consumption ofpiperidin-4-amine, the reaction mixture was diluted with water (5 mL)and extracted with DCM (2×15 mL). The combined organic extract waswashed with a saturated solution of aqueous NaHCO₃ (8.0 mL), water (5.0mL) and dried over anhydrous sodium sulphate. The organic layer wasfiltered and concentrated at rotavapor to give2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-4-yl)acetamide(0.18 g, 55.04% yield) as white solid. LCMS (ES) m/z=437.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.33 (m, 1H), 1.43-1.46 (m, 1H),1.71-1.74 (m, 2H), 2.70-2.79 (m, 1H), 3.09-3.16 (m, 1H), 3.76-3.79 (m,1H), 3.88-3.90 (m, 1H), 4.18-4.21 (m, 1H), 4.46 (s, 2H), 4.80-4.83 (m,2H), 6.95 (dd, J=9.2 Hz, 4H), 7.32 (t, J=9.2 Hz, 4H), 8.02 (d, J=7.6 Hz,1H).

Example 22-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)acetamide

Step 1:

To a solution of 4-chlorophenol (5 g, 38.89 mmol, 1 equiv) in DMF (60mL) was added anhydrous potassium carbonate (6.44 g, 46.67 mmol, 1.2equiv) and 1,3-dibromopropane (5.94 mL, 58.34 mmol, 1.5 equiv). Thereaction mixture was stirred at room temperature for 16 h. Reactionmixture was diluted with water (20 mL) and extracted with EtOAc (2×150mL). The combined organic extract was washed with cold water (100 mL)followed by a saturated brine solution (50 mL), dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure togive the crude product. The crude product was purified by flash columnchromatography using a silica gel column and a mixture of ethyl acetateand hexane as eluent and the product was eluted at 2-3% EtOAc in hexane.Fractions containing product were concentrated to give1-(3-bromopropoxy)-4-chlorobenzene (3.8 g, 39.25% yield) as colorlessliquid. LCMS (ES) m/z=248.0, 250.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δppm 2.27-2.33 (m, 2H), 3.59 (t, J=6.4 Hz, 2H), 4.07 (t, J=5.6 Hz, 2H),6.83 (d, J=8.8 Hz, 2H), 7.22-7.24 (m, 2H).

Step 2:

To a solution of tert-butyl piperidin-4-ylcarbamate (0.5 g, 2.49 mmol, 1equiv) in DMF (10 mL) was added cesium carbonate (0.976 g, 2.99 mmol,1.2 equiv) and 1-(3-bromopropoxy)-4-chlorobenzene (0.747 g, 2.99 mmol,1.2 equiv). The reaction mixture was stirred at room temperature for 13h. The reaction mixture was diluted with water (10 mL) and extractedwith EtOAc (2×25 mL). The combined organic extract was washed with asaturated brine solution (10 mL), dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to give the crudeproduct. The crude product was purified by flash column chromatographyusing a silica gel column and mixture of ethyl acetate in hexane aseluent. The product was eluted at 58-62% ethylacetate in hexane.Fractions containing product were concentrated under reduced pressure togive tert-butyl (1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)carbamate(0.510 g, 55.43% yield) as color less liquid. LCMS (ES) m/z=369.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.34 (m, 11H), 1.62-1.65(m, 2H), 1.78-1.89 (m, 4H), 2.34 (t, J=7.2 Hz, 2H), 2.75-2.78 (m, 2H),3.15 (s, 1H), 3.94 (t, J=6.0 Hz, 2H), 6.73 (d, 7.6 Hz, 1H), 6.92 (d,J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H).

Step 3:

To a solution of tert-butyl(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)carbamate (0.510 g, 1.38mmol, 1 equiv) in DCM (12 mL) at 0° C. was added 4 M HCl in dioxane (8mL) and the reaction mixture allowed to stir at room temperature for 12h. After consumption of the starting material, solvent was evaporatedunder reduced pressure. The solid obtained was triturated with Et₂O (10mL). The ether layer was decanted and the solid was dried under highvacuum to give 1-(3-(4-chlorophenoxy)propyl)piperidin-4-aminehydrochloride (0.380 g, 89.8% yield) as white solid. LCMS (ES) m/z=269.3[M+H]⁺.

Step 4:

To 1-(3-(4-chlorophenoxy)propyl)piperidin-4-amine hydrochloride (0.120g, 0.393 mmol, 1 equiv) in DCM (10 mL) at 0° C. was added triethylamine(0.165 mL, 1.179 mmol, 3 equiv) and 2-(4-chlorophenoxy)acetic acid(0.088 g, 0.471 mmol, 1.2 equiv). After the reaction mixture was stirredfor 5 minutes at 0° C., T₃P (50 wt. % in ethyl acetate) (0.374 mL, 0.587mmol, 1.5 equiv) was added and the reaction mixture was stirred at roomtemperature for 14 h. The reaction mixture was then diluted with water(8 mL) and extracted with DCM (2×10 mL). The combined organic extractwas washed with saturated aqueous NaHCO₃ solution (10 mL) and water (10mL). The organic phase was dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to give the crudeproduct which was purified by flash column chromatography using a silicagel column and methanol in DCM as eluent. The product was eluted at 3-4%methanol in DCM. Fractions containing the product were concentratedunder reduced pressure and dried under high vacuum to give2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)acetamide(0.072 g, 42.1% yield) as off white solid. LCMS (ES) m/z=437.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41-1.48 (m, 2H), 1.64-1.67 (m, 2H),1.79-1.83 (m, 2H), 1.90-1.95 (m, 2H), 2.36 (t, J=6.4 Hz, 2H), 2.76-2.79(m, 2H), 3.57-3.59 (m, 1H), 3.95 (t, J=6.0 Hz, 2H), 4.43 (s, 2H),6.91-6.95 (m, 4H), 7.27-7.32 (m, 4H), 7.93 (d, J=8.0 Hz, 1H).

Examples 3 to 8

The Compounds of Examples 3 to 8 were prepared generally according tothe procedures described above for Examples 1 and 2.

TABLE 1 LCMS Cmpd m/z ¹H-NMR (400 # Structure Name [M + H]⁺ MHz,DMSO-d₆) 3

8-(2-(4- chlorophenoxy) acetyl)-3- (2-(4- chlorophenoxy) ethyl)-1-oxa-3,8- diazaspiro[4.5] decan-2- one 479.1 1.64-1.70 (m, 2H), 1.74-1.79(m, 2H), 3.21- 3.26 (m, 1H), 3.38-3.39 (m, 1H), 3.44 (s, 2H), 3.50-3.53(m, 3H), 3.77-3.80 (m, 1H), 4.11 (t, J = 10 Hz, 2H), 4.83 (s, 2H), 6.92-6.98 (m, 4H), 7.28-7.33 (m, 4H). 4

2-(4- chlorophenoxy)- N-(1-(2-(4- chlorophenoxy) acetyl)piper- idin-3-yl)acetamide 451.0 1.31-1.37 (m, 1H), 1.52-1.55 (m, 1H), 1.66 (bs, 2H),2.30-2.38 (m, 1H), 2.58- 2.64 (m, 1H), 2.98-3.04 (m, 1H), 3.37-3.39 (m,2H), 3.77- 3.80 (m, 1H), 3.94-3.97 (m, 2H), 4.22-4.26 (m, 1H), 4.75-4.84 (m, 2H), 6.90-6.95 (m, 4H), 7.28-7.30 (m, 4H), 8.02 (s, 1H). 5

N-(2-(4- chlorophenoxy) ethyl)-1-(3- (4- chlorophenoxy) propanoyl)piperidine-4- carboxamide 465.3 1.33-1.39 (m, 1H), 1.48-1.54 (m, 1H),1.63- 1.66 (m, 2H), 2.37- 2.48 (m, 1H), 2.54-2.64 (m, 1H), 2.71-2.81 (m,2H), 2.97- 3.00 (m, 1H), 3.37-3.39 (m, 2H), 3.87-3.96 (m, 3H), 4.16 (s,2H), 4.31-4.36 (m, 1H), 6.91- 6.94 (m, 4H), 7.27-7.30 (m, 4H), 8.01 (s,1H). 6

2-(4- chlorophenoxy)- N-(1-(3-(4- chlorophenoxy) propanoyl) piperidin-4-yl)acetamide 451.1 1.28-1.34 (m, 1H), 1.38-1.41 (m, 1H), 1.68- 1.76 (m,2H), 2.65-2.70 (m, 1H), 2.73-2.78 (m, 2H), 3.07- 3.13 (m, 1H), 3.84-3.87(m, 2H), 4.15-4.17 (m, 2H), 4.26- 4.27 (m, 1H), 4.45 (s, 2H), 6.93 (t, J= 9.2 Hz, 4H), 7.30 (t, J = 12 Hz, 4H), 7.98-8.0 (m, 1H). 7

2-(4- chlorophenoxy)- N-(1-(2-(4- chlorophenoxy) ethyl)piperi- din-4-yl)acetamide 423.3 1.42-1.50 (m, 2H), 1.65 (d, J = 10.4 Hz, 2H), 2.07(t, J = 10.8 Hz, 2H), 2.63 (d, J = 5.6 Hz, 2H), 2.83 (d, J = 11.6 Hz,2H), 3.57 (br. s., 1H), 4.02 (t, J = 5.6 Hz, 2H), 4.43 (s, 2H), 6.94 (d,J = 7.6 Hz, 4H), 7.27-7.32 (m, 4H), 7.90 (d, J = 7.6 Hz, 1H). 8

2-(4- chlorophenoxy)- N-((1-(2- (4- chlorophenoxy) acetyl)piperi- din-4-yl)meth- yl)acetamide 451.1 0.90-0.93 (m, 1H), 1.06-1.09 (m, 1H), 1.55-1.67 (m, 3H), 2.47-2.52 (m, 1H), 2.91-3.01 (m, 3H), 3.76 (d, J = 13.2Hz, 1H), 4.23 (q, J = 12.4 Hz, 1H), 4.46 (s, 2H), 4.77 (q, J = 11.4 Hz,2H), 6.90 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 7.27-7.33 (m,4H), 8.09 (br. s., 1H).

Example 9N-(1-(2-((5-chloroisothiazol-3-yl)oxy)ethyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide

Step 1:

To a stirred solution of 5-chloroisothiazol-3(2H)-one (0.3 g, 2.21 mmol,1 equiv) in THF was added DBU (0.6 mL, 4.42 mmol, 2 equiv) drop wiseunder cooling condition, it was stirred for 5 mins at 0° C., after that1,2-dibromoethane (0.4 mL, 4.42 mmol, 2 equiv) was added drop wise undercooling condition, reaction mixture was stirred at room temperature for3 hours, reaction mixture was quenched with saturated NH₄Cl solution,aqueous layer was extracted with (2×15 mL) of ethyl acetate, combinedorganic layers were dried over under anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to get crude product, crude productwhich was purified by silicagel column chromatography using 7-8% ethylacetate in hexane as an eluent to get afford titled compound3-(2-bromoethoxy)-5-chloroisothiazole (0.06 g, 11.21%, Brown solid). 1HNMR (400 MHz, CDCl₃-d6): δ 3.63-3.66 (m, 2H), 4.61-4.64 (m, 2H), 6.56(s, 1H).

Step 2:

To a stirred solution of 3-(2-bromoethoxy)-5-chloroisothiazole (0.059 g,0.24 mmol, 1.5 equiv) in ACN (10 mL) was added Cesium carbonate (0.13 g,0.4 mmol, 2.5 equiv), TEA (0.06 mL, 0.40, 2.5 equiv) and2-(4-chlorophenoxy)-N-(piperidin-4-yl)acetamide hydrochloride (0.05 g,0.16 mmol, 2.5 equiv) poration wise at 0° C. Then reaction mixture wasstirred at 85° C. for 4 hours. Reaction mixture was diluted with icecold water (20 mL), extracted with (2×25 mL) ethyl acetate. Combinedorganic layer was dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure, Crude product which was purified byPrep TLC using 5% MeOH in DCM as an eluent to get afford titled compoundN-(1-(2-((5-chloroisothiazol-3-yl)oxy)ethyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide(0.0051 g, 7.2%, Light yellow solid), LCMS (ES) m/z=430 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6): δ 1.40-1.48 (m, 2H), 1.63-1.66 (m, 2H), 2.02-2.08(m, 2H), 2.64-2.65 (m, 2H), 2.81-2.84 (m, 2H), 3.57-3.59 (m, 1H),4.32-4.35 (m, 2H), 4.43 (s, 2H), 6.95 (d, J=8.8 Hz, 2H), 7.04 (s, 1H),7.32 (d, J=8.8 Hz, 2H), 7.90 (d, J=7.6 Hz, 1H).

The Compounds of Example 10 was prepared generally according to theprocedures described above for Example 9.

TABLE 2 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 9

N-(1-(2-((5- chloroisothiazol- 3- yl)oxy)ethyl)piperi- din-4-yl)-2- (4-chlorophenoxy) acetamide 430 1.40-1.48 (m, 2 H), 1.63- 1.66 (m, 2 H),2.02-2.08 (m, 2 H), 2.64-2.65 (m, 2 H), 2.81- 2.84 (m, 2 H), 3.57-3.59(m, 1 H), 4.32-4.35 (m, 2 H), 4.43 (s, 2 H), 6.95 (d, J = 8.8 Hz, 2 H),7.04 (s, 1 H), 7.32 (d, J = 8.8 Hz, 2 H), 7.90 (d, J = 7.6 Hz, 1 H). 10

N-(1-(3-((5- chloroisothiazol- 3- yl)oxy)propyl) piperidin-4-yl)- 2-(4-chlorophenoxy) acetamide 441.1 1.44-1.46 (m, 2 H), 1.65- 1.67 (m, 2 H),1.78-1.85 (m, 2 H), 1.93 (bs, 2 H), 2.30-2.40 (m, 2 H), 2.77 (bs, 2 H),3.58 (bs, 1 H), 4.28 (t, J = 6.2 Hz, 2 H), 4.43 (s, 2 H), 6.94 (d, J =8.4 Hz, 2 H), 7.01 (s, 1 H), 7.31 (d, J = 8.8 Hz, 2 H), 7.90 (d, J = 6.8Hz, 1 H).

Example 112-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide

Step 1:

To a stirred solution of 4-chlorophenol (1.0 g, 7.78 mmol) in acetone(50 mL) was added potassium carbonate (3.2 g, 23.33 mmol) followed by2-(chloromethyl)oxirane (2.4 mL, 31.11 mmol) drop wise and the reactionmixture was refluxed for 16 h. After completion of the reaction,reaction mixture was filtered by sintered funnel and concentrated underreduced pressure and the crude was purified by silica-gel columnchromatography by using 8% EA: Hex Yield: 1.3 g (85.71%) as pale yellowliquid. ¹H NMR (400 MHz, CDCl3): δ ppm: 2.74-2.75 (m, 1H), 2.89-2.91 (m,1H), 3.32-3.35 (m, 1H), 3.9-3.94 (m, 1H), 4.21 (dd, J1=10.8 Hz, J2=2.8Hz, 1H), 6.83-6.87 (m, 2H), 7.19-7.24 (m, 2H).

Step 2:

To a stirred solution of 2-(4-chlorophenoxy)-N-(piperidin-4-yl)acetamidehydrochloride (1.0 g, 3.27 mmol) in ethanol (20 mL) was addedtriethylamine (0.91 mL, 6.55 mmol) followed by2-((4-chlorophenoxy)methyl)oxirane (0.91 g, 4.91 mmol) and the reactionmixture was stirred at rt (29° C.) for 16 h. After completion of thereaction, reaction mixture was concentrated under reduced pressure andthe crude product was purified by silica-gel column chromatography byusing 4% MeOH:DCM as an eluent to get the product and the position ofthe hydroxyl group was confirmed by 13NMR, COSY, HSQC and HMBC NMR.Yield: 0.9 g (60.8%) as a white solid. LC-MS (ES) m/z: 453.6 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ ppm: 1.42-1.5 (m, 2H), 1.63-1.66 (m, 2H),2.01-2.09 (m, 2H), 2.29-2.48 (m, 2H), 2.77-2.85 (m, 2H), 3.57-3.59 (m,1H), 3.81-3.85 (m, 1H), 3.88-3.89 (m, 1H), 3.94-3.96 (m, 1H), 4.43 (s,2H), 4.78 (d, J=4.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 4H), 7.30 (t, J=8.8 Hz,4H), 7.89 (d, J=8.0 Hz, 1H).

The Compounds of Examples 12 and 13 were prepared generally according tothe procedures described above for Example 11.

TABLE 3 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 11

2-(4- chlorophenoxy)- N-(1-(3-(4- chlorophenoxy)- 2- hydroxypropyl)piperidin-4- yl)acetamide 453.6 1.42-1.50 (m, 2 H), 1.63- 1.66 (m, 2 H),2.01-2.09 (m, 2H), 2.29-2.48 (m, 2 H), 2.77-2.85 (m, 2 H), 3.57- 3.59(m, 1 H), 3.81-3.85 (m, 1 H), 3.88-3.89 (m, 1 H), 3.94- 3.96 (m, 1 H),4.43 (s, 2 H), 4.78 (d, J = 4.0 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 4 H),7.30 (t, J = 8.8 Hz, 4 H), 7.89 (d, J = 8.0 Hz, 1 H). 12

(R)-2-(4- chlorophenoxy)- N-(1-(3-(4- chlorophenoxy)- 2- hydroxypropyl)piperidin-4- yl)acetamide 453.1 1.42-1.49 (m, 2 H), 1.63 (bs, 2 H),2.09-2.01 (m, 2 H), 2.31-2.42 (m, 2 H), 2.77- 2.85 (m, 2 H), 3.57-3.59(m, 1 H), 3.81-3.96 (m, 3 H), 4.43 (s, 2 H), 4.78 (d, J = 4.4 Hz, 1 H),6.94 (d, J = 8.8 Hz, 4 H), 7.3 (t, J = 8.8 Hz, 4 H), 7.89 (d, J = 7.6Hz, 1 H). 13

(S)-2-(4- chlorophenoxy)- N-(1-(3-(4- chlorophenoxy)- 2- hydroxypropyl)piperidin-4- yl)acetamide 453.1 1.42-1.49 (m, 2 H), 1.63 (bs, 2 H),2.09-2.01 (m, 2 H), 2.31-2.42 (m, 2 H), 2.77- 2.85 (m, 2 H), 3.57-3.59(m, 1 H), 3.81-3.96 (m, 3 H), 4.43 (s, 2 H), 4.78 (d, J = 4.4 Hz, 1 H),6.94 (d, J = 8.8 Hz, 4 H), 7.32-7.28 (m, 4 H), 7.89 (d, J = 7.6 Hz, 1H).

Example 142-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-fluoropropyl)piperidin-4-yl)acetamide

Step 1:

To a stirred solution of2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide(0.05 g, 0.11 mmol) in DCM, DAST (0.03 mL, 0.22 mmol) was added at 0° C.and followed by ethanol 0.1 mL was added and stirred the reactionmixture was stirred at rt (29°) for 16 h. After completion of thereaction, reaction mixture was quenched with DCM 5 mL, and diluted withwater 50 mL and extracted with DCM 50 mL×2, the combined organic layerwas washed with sodium bicarbonate solution and dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure and the crudeproduct was purified by prep. TLC by using 50% EA: Hex as an eluent toget the product. Yield: 0.0119 g (11.9%) as a white solid. LC-MS (ES)m/z: 455.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.43-1.51 (m, 2H),1.64-1.67 (m, 2H), 2.11-2.13 (m, 2H), 2.58-2.58 (m, 2H), 2.81-2.84 (m,2H), 3.58-3.6 (m, 1H), 4.06-4.23 (m, 2H), 4.44 (s, 2H), 4.88-5.0 (m,1H), 6.96 (t, J=10.0 Hz, 4H), 7.31 (d, J=8.8 Hz, 4H), 7.90 (d, J=7.2 Hz,1H).

TABLE 4 Cmpd LCMS m/z # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 14

2-(4- chlorophenoxy)- N-(1-(3-(4- chlorophenoxy)- 2-fluoropropyl)piperi- din-4- yl)acetamide 455.1 1.43-1.51 (m, 2 H), 1.64-1.67 (m, 2 H), 2.11-2.13 (m, 2 H), 2.58-2.58 (m, 2 H), 2.81-2.84 (m, 2H), 3.58- 3.6 (m, 1H), 4.06-4.23 (m, 2 H), 4.44 (s, 2 H), 4.88-5.0 (m, 1H), 6.96 (t, J = 10.0 Hz, 4 H), 7.31 (d, J = 8.8 Hz, 4 H), 7.90 (d, J =7.2 Hz, 1 H).

Example 152-(4-chlorophenoxy)-N-(2-(3-(4-chlorophenoxy)-2-hydroxypropyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide

Step 1:

To 2-(4-chlorophenoxy)acetic acid (0.52 g, 1.81 mmol, 2.83 equiv) in DCM(15 mL) at 0° C. was added triethylamine (0.78 mL, 5.66 mmol, 3.0 equiv)and was stirred for 5 minutes at 0° C., T3P (50 wt % in ethyl acetate)(2.4 mL, 3.77 mmol, 2 equiv) was added and the reaction mixture wasstirred at 0° for 10 mins. After that tert-butyl5-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.4 g, 1.88 mmol, 1.0equiv.) was added to the reaction mixture, reaction mixture was stirredat room temperature for 12 hours. The reaction mixture was then dilutedwith water (15 mL) and extracted with DCM (2×10 mL). The combinedorganic extract was washed with saturated aqueous NaHCO₃ solution (10mL) and water (15 mL), precipitated the solid, precipitated was filteredthrough a sintered funnel, washed with ice-cold water (10 mL), finallywashed with n-pentane (100 mL) dried under high vacuum to give to givetert-butyl5-(2-(4-chlorophenoxy)acetamido)-2-azabicyclo[2.2.1]heptane-2-carboxylate(0.7 g, 98%, as a Brown liquid) LC-MS: 381 [M+H]⁺, 1H NMR (400 MHz,DMSO-d6): δ 1.30-1.36 (m, 9H), 1.50-1.51 (m, 2H), 1.52-1.53 (m, 1H),1.96-2.10 (m, 2H), 3.00-3.32 (m, 2H), 4.00-4.03 (m, 2H), 4.45-4.50 (m,2H), 6.92-6.95 (m, 2H), 7.32 (d, J=6.4 Hz, 2H), 8.03-8.21 (m, 1H).

Step 2:

To a solution of tert-butyl5-(2-(4-chlorophenoxy)acetamido)-2-azabicyclo[2.2.1]heptane-2-carboxylate(0.7 g, 1.84 mmol, 1.0 equiv) in DCM (15 mL) was added and 4.0 M indioxane.HCl (10 mL) was added and stirred it for 12 h. After consumptionof the starting material (TLC, 5% Methanol in DCM), DCM was evaporatedunder reduced pressure. The solid obtained was triturated with n-pentane(10 mL), diethyl ether (10 mL), dried under high vacuum to giveN-(2-azabicyclo[2.2.1]heptan-5-yl)-2-(4-chlorophenoxy)acetamidehydrochloride (0.55 g, crude). LC-MS: 281 [M+H]⁺ (free base) 1H NMR (400MHz, DMSO-d6): δ 1.53-1.61 (m, 1H), 1.66-1.69 (m, 1H), 1.78-1.83 (m,1H), 2.03-2.17 (m, 1H), 2.65-2.69 (m, 1H), 2.85-2.90 (m, 1H), 2.91-2.98(m, 1H), 3.00-3.19 (m, 0.5H), 3.20-3.32 (m, 0.5H), 3.81-3.90 (m, 0.5H),3.94-4.00 (m, 1H), 4.15-4.16 (m, 0.5H), 4.47-4.51 (m, 2H), 6.95 (d,J=8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.31-7.34 (m, 2H), 8.17-8.21 (m,1H), 8.36 (bs, 1H), 8.79 (bs, 1H).

Step 3:

To a stirred solution of compoundN-(2-azabicyclo[2.2.1]heptan-5-yl)-2-(4-chlorophenoxy)acetamidehydrochloride (0.15 g, 0.47 mmol, 1 equiv) in ethanol was added TEA (0.2mL, 1.41 mmol, 3 equiv) drop wise under cooling condition, reactionmixture was stirred for 5 mins, after that2-((4-chlorophenoxy)methyl)oxirane (0.10 g, 0.56 mmol, 1.2 equiv) wasadded to reaction mixture drop wise under cooling condition, reactionmixture was stirred at room temperature (29° C.) for 12 hours, aftercompletion of the reaction, reaction mass was evaporated under reducedpressure to get the crude product, obtained crude was quenched with 10mL of water, extracted with (2×15 mL) of DCM, combined organic layerswere washed with 10 mL of brine, organic layer was dried over underanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toget the crude product. The crude product which was purified by silicagelcolumn chromatography using 5% MeOH in DCM as an eluent to give the2-(4-chlorophenoxy)-N-(2-(3-(4-chlorophenoxy)-2-hydroxypropyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamid,0.05 g (22.72%, as gummy solid), LC-MS: 465.1 [M+H]+, 1H NMR (400 MHz,DMSO-d6): δ 1.27-1.30 (m, 0.5H), 1.40-1.47 (m, 2H), 1.62-1.64 (m, 1H),1.79-1.88 (m, 1H), 2.07-2.17 (m, 1H), 2.47 (s, 1H), 2.48 (s, 1H), 2.65(s, 0.5H), 2.20-2.30 (m, 0.5H), 3.12-3.32 (m, 1H), 3.60-3.70 (m, 0.5H),3.80-3.86 (m, 2H), 3.94-4.00 (m, 2H), 4.43-4.49 (m, 2H), 4.60-4.90 (m,1H), 6.92-6.95 (m, 4H), 7.28-7.32 (m, 4H), 7.91-8.04 (m, 1H).

TABLE 5 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 15

2-(4- chlorophenoxy)- N-(2-(3-(4 chlorophenoxy)- 2- hydroxypropyl)- 2-azabicyclo[2.2.1] heptan-5- yl)acetamide 465.1 1.27-1.30 (m, 0.5 H),1.40- 1.47 (m, 2 H), 1.62-1.64 (m, 1 H), 1.79-1.88 (m, 1 H), 2.07-2.17(m, 1 H), 2.47 (s, 1 H), 2.48 (s, 1 H), 2.65 (s, 0.5 H), 2.20-2.30 (m,0.5 H), 3.12-3.32 (m, 1 H), 3.60- 3.70 (m, 0.5 H), 3.80-3.86 (m, 2 H),3.94-4.00 (m, 2 H), 4.43-4.49 (m, 2 H), 4.60- 4.90 (m, 1 H), 6.92-6.95(m, 4 H), 7.28-7.32 (m, 4H), 7.91-8.04 (m, 1 H).

Example 162-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-methoxypropyl)piperidin-4-yl)acetamide

Step 1:

To a stirred solution of 24-chlorophenol (2.0 g, 15.56 mmol, 1 equiv) inwater (20 mL), triethylamine (6.5 mL, 46.67 mmol, 3 equiv) was added thereaction mixture was stirred at rt (27°) for 16 h. After completion ofthe reaction, reaction mixture was extracted with DCM 50 mL×2, thecombined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to get the crudeproduct. The crude product was purified by silica gel columnchromatography by using 8% EA: Hex. Yield: 1.5 g (34.88%) as colorlessliquid. ¹H NMR (400 MHz, CDCl₃): δ ppm: 1.21 (t, J=6.8 Hz, 3H), 1.25 (t,J=7.2 Hz, 3H), 3.57-3.65 (m, 2H), 3.75-3.84 (m, 2H), 3.96 (bs, 1H),4.00-4.04 (m, 1H), 4.11-4.15 (m, 1H), 4.60 (d, J=5.6 Hz, 1H), 6.87 (d,J=9.2 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H).

Step 2:

To a stirred solution of 3-(4-chlorophenoxy)-1,1-diethoxypropan-2-ol(1.5 g, 5.45 mmol, 1 equiv) in THF (10 mL), 60% NaH (0.44 g, 21.82 mmol,4 equiv) was added at 0° C. and stirred the reaction mixture at rt (27°)for 30 min. Finally methyl iodide was added to the reaction mixture at0° C. and allowed the reaction mixture to stir at rt (27° C.) for 2 h.After completion of the reaction, reaction mixture was quenched with iceand extracted with ethyl acetate 100 mL, the organic layer was separatedand dried over anhydrous sodium sulphate, filtered and concentratedunder reduced pressure to get the crude product. The crude product waspurified by silica gel column chromatography by using 9% EA; Hex. Yield:1.3 g (82.80%) as colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ ppm: 1.19(t, J=7.2 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 3.53-3.55 (m, 5H), 3.58-3.67(m, 1H), 3.71-3.78 (m, 2H), 4.02-4.06 (m, 1H), 4.19 (dd, J=2.4, 10.4 Hz,1H), 4.57 (d, J=5.2 Hz, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz,2H).

Step 3:

To a stirred solution of1-chloro-4-(3,3-diethoxy-2-methoxypropoxy)benzene (1.0 g, 3.46 mmol, 1.0equiv) in acetone (10 mL), 2N HCl (10 mL) was added drop wise at rt (27°C.) and heated the reaction mixture at 50° C. for 16 h. After completionof the reaction, reaction mixture was concentrated under reducedpressure and diluted the crude with 10 mL of water and extracted withDCM (50 mL×2), the combined organic layer was dried over anhydroussodium sulphate, filtered and concentrated to get the crude product andthe crude product was carried to next step without any purification.Weight: 0.7 g crude as brown liquid. ¹H NMR (400 MHz, CDCl₃): δ ppm:3.59 (s, 1H), 3.95 (s, 1H), 4.17-4.26 (m, 1H), 4.26-4.29 (m, 1H), 6.84(d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 9.81 (s, 1H).

Step 4: 2-(4-chlorophenoxy)-N-(piperidin-4-yl)acetamide hydrochloridewas taken in 20 mL of DCM and cooled to 0° C. and added saturatedsolution of sodium bicarbonate solution to pH=7 and then extracted withDCM, organic layer was dried over anhydrous sodium sulphate, filteredand concentrated to get the pre base amine. To a solution of2-(4-chlorophenoxy)-N-(piperidin-4-yl)acetamide (0.15 g, 0.491 mmol, 1equiv) in dichloroethane, 3-(4-chlorophenoxy)-2-methoxypropanal (0.21 g,0.982 mmol, 2 equiv) was added followed by 3 drops of acetic acid wereadded and stirred at rt (27° C.) for 30 min. Finally to the suspensionsodium cyanoborohydride was added and stirred the reaction mixture at rt(27° C.) for 16 h. After completion of the reaction, reaction mixturewas diluted with 50 mL of water and extracted with DCM (50 mL×2), thecombined organic layer was dried over anhydrous sodium sulphate,filtered and concentrated to get the crude product and the crude productwas purified by prep TLC by using 5% MeOH:DCM as an eluent to get thepure product. Yield: 0.021 g (9.5%), as white solid. LC-MS (ES) m/z:467.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ ppm: 1.41-1.49 (m, 2H),1.63-1.70 (m, 2H), 2.42-2.43 (m, 2H), 2.81 (t, J=10.8 Hz, 2H), 3.33 (s,3H), 2.6-3.59 (m, 2H), 3.96-3.92 (m, 1H), 4.07 (dd, J=3.2, 10.4 Hz, 1H),4.43 (s, 2H), 6.94-6.97 (m, 4H), 7.29-7.33 (m, 4H), 7.88 (d, J=7.6 Hz,1H).

TABLE 6 LCMS m/z ¹H-NMR (400 MHz, DMSO- Cmpd # Structure Name [M + H]⁺d₆) 16

2-(4- chlorophenoxy)- N-(1-(3-(4- chlorophenoxy)- 2- methoxypropyl)piperidin-4- yl)acetamide 467.1 1.41-1.49 (m, 2 H), 1.63- 1.70 (m, 2 H),2.42-2.43 (m, 2 H), 2.81 (t, J = 10.8 Hz, 2 H), 3.33 (s, 3 H), 2.60-3.59 (m, 2 H), 3.96-3.92 (m, 1 H), 4.07 (dd, J = 3.2, 10.4 Hz, 1 H),4.43 (s, 2 H), 6.94-6.97 (m, 4 H), 7.29- 7.33 (m, 4 H), 7.88 (d, J = 7.6Hz, 1 H).

Example 172-(4-chlorophenoxy)-N-(1-(3-((6-chloropyridin-3-yl)oxy)propyl)piperidin-4-yl)acetamide

Step 1:

To a solution of 6-chloropyridin-3-ol (0.3 g, 2.315 mmol, 1.0 equiv) inN,N-dimethylformamide (5 mL) was added potassium carbonate (0.48 g,3.473 mmol, 1.5 equiv) and 1,3-dibromopropane (0.48 g, 3.473 mmol, 1.5equiv) at 27° C. The resulting mixture was stirred at 27° C. for 16 h.The progress of the reaction was monitored by TLC. After completion ofreaction, the reaction mixture was diluted with water (50 mL), extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith cold water (50 mL), brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to get thecrude product. The crude product was purified by silicagel columnchromatography using 10% ethyl acetate in hexane as eluent to obtain thetitle compound 5-(3-bromopropoxy)-2-chloropyridine (0.3 g, crude) aswhite solid. LCMS (ES) m/z=250 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ ppm2.30-2.36 (m, 2H), 3.59 (t, J=1.7 Hz, 2H), 4.14 (t, J=6.0 Hz, 2H),7.18-7.22 (m, 2H), 8.07 (d, J=1.6 Hz, 1H).

Step 2:

To a stirred solution of 2-(4-chlorophenoxy)-N-(piperidin-4-yl)acetamidehydrochloride (0.1 g, 0.327 mmol, 1.0 equiv) in N,N-dimethylmethanamide(10 mL) was added cesium carbonate (0.16 g, 0.491 mmol, 1.5 equiv),triethyl amine (0.09 mL, 0.655 mmol, 2.0 equiv) and5-(3-bromopropoxy)-2-chloropyridine (0.098 g, 0.393 mmol, 1.2 equiv) at27° C. The resulting mixture was stirred at 27° C. for 16 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, the reaction mixture was diluted with water (50 mL), theproduct was extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with cold water (25 mL), brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to get the crude product. The crude product was purified bysilicagel column chromatography using 5% methanol in dichloromethane aseluent to obtain the title compound2-(4-chlorophenoxy)-N-(1-(3-((6-chloropyridin-3-yl)oxy)propyl)piperidin-4-yl)acetamide(0.07 g, 48.9% yield) as white solid. LCMS (ES) m/z=438.3 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.41-1.49 (m, 2H), 1.65-1.67 (m, 2H),1.82-1.85 (m, 2H), 1.91-1.97 (m, 2H), 2.38 (t, J=6.4 Hz, 2H), 2.78 (d,J=11.2 Hz, 2H), 3.58-3.59 (m, 1H), 4.06 (t, J=6.4 Hz, 2H), 4.43 (s, 2H),6.95 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 1H),7.44-7.47 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H).

The Compounds of Examples 18 and 19 were prepared generally according tothe procedures described above for Example 17.

TABLE 7 LCMS m/z ¹H-NMR (400 MHz, DMSO- Cmpd # Structure Name [M + H]⁺d₆) 17

2-(4- chlorophenoxy)- N-(1-(3-((6- chloropyridin-3- yl)oxy)propyl)piperidin-4- yl)acetamide 438.3 1.41-1.49 (m, 2 H), 1.65- 1.67 (m, 2 H),1.82-1.85 (m, 2 H), 1.91-1.97 (m, 2 H), 2.38 (t, J = 6.4 Hz, 2 H), 2.78(d, J = 11.2 Hz, 2 H), 3.58-3.59 (m, 1 H), 4.06 (t, J = 6.4 Hz, 2 H),4.43 (s, 2 H), 6.95 (d, J = 8.8 Hz, 2 H), 7.31 (d, J = 8.8 Hz, 2 H),7.39 (d, J = 8.8 Hz, 1 H), 7.44-7.47 (m, 1 H), 7.90 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1 H). 18

2-(4- chlorophenoxy)- N-(2-(3-(4- chlorophenoxy) propyl)-2-azabicyclo[2.2.1] heptan-5- yl)acetamide 449.1 1.23-1.54 (m, 2 H), 1.55-1.64 (m, 1 H), 1.65-1.90 (m, 3 H), 1.92-2.15 (m, 2 H), 2.34-2.42 (m, 2H), 2.50-2.62 (m, 1 H), 2.90- 3.12 (m, 1 H), 3.60-3.70 (m, 0.5 H),3.88-3.95 (m, 0.5 H), 3.98 (d, J = 4.4 Hz, 2 H), 4.47 (d, J = 22.8 Hz, 2H), 6.92-6.94 (m, 4 H), 7.28-7.32 (m, 4 H), 7.97 (bs, 1 H), 8.82 (bs,0.2 H). 19

N-(1-(3-(4- chlorophenoxy) propyl)piperidin- 4-yl)-2-((5-chloropyridin-2- yl)oxy)acetamide 438.1 1.36-1.44 (m, 2 H), 1.63- 1.66(m, 2 H) 1.81 (t, J = 6.8 Hz, 2 H), 1.92 (t, J = 11.2 Hz, 2 H), 2.36 (t,J = 6.8 Hz, 2 H), 2.75-2.78 (m, 2 H), 3.53-3.55 (m, 1 H), 3.96 (t, J =6.0 Hz, 2 H), 4.65 (s, 2 H), 6.91- 6.94 (m, 3 H), 7.28 (d, J = 8.8 Hz, 2H), 7.79-7.85 (m, 2 H), 8.14 (s, 1 H).

Example 202-(4-chlorophenoxy)-N-(1-(3-((5-chloropyridin-2-yl)oxy)propyl)piperidin-4-yl)acetamide

Step 1:

To a mixture of 2-(4-chlorophenoxy)-N-(piperidin-4-yl)acetamidehydrochloride (0.5 g, 1.638 mmol, 1.0 equiv) in dichloromethane (20 mL)was added potassium carbonate (0.45 g, 3.276 mmol, 2.0 equiv) and1-bromo-3-chloropropane (0.51 g, 3.276 mmol, 2.0 equiv) at 27° C., theresulting mixture was stirred for 24 h. The progress of the reaction wasmonitored by TLC. After completion of reaction, the reaction mixture wasdiluted with water (50 mL), the product was extracted with ethyl acetate(3×200 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to get thecrude product. The crude product was purified by silicagel columnchromatography using 4% methanol in dichloromethane as eluent to obtainthe title compound2-(4-chlorophenoxy)-N-(1-(3-chloropropyl)piperidin-4-yl)acetamide (0.21g, 37% yield) as off white solid. LCMS (ES) m/z=345.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.41-1.48 (m, 2H), 1.64-1.67 (m, 2H),1.81-1.84 (m, 2H), 1.91-1.96 (m, 2H), 2.30-2.36 (m, 2H), 2.65-2.73 (m,2H), 3.61-3.64 (m, 3H), 4.43 (s, 2H), 6.95 (d, J=8.8 Hz, 2H), 7.32 (d,J=8.8 Hz, 2H), 7.90 (d, J=8.0 Hz, 1H).

Step 2:

In microwave vial, to a stirred solution of2-(4-chlorophenoxy)-N-(1-(3-chloropropyl)piperidin-4-yl)acetamide (0.15g, 0.434 mmol, 1.0 equiv) in N,N-dimethylmethanamide (3 mL) was addedsilver carbonate (0.24 g, 0.868 mmol, 2.0 equiv) and5-chloropyridin-2-ol (0.056 g, 0.434 mmol, 1.0 equiv) at 27° C. Theresulting mixture was subjected to microwave irradiation at 80° C. for 1h. The progress of the reaction was monitored by TLC. After completionof reaction, the reaction mixture was filtered through celite pad,washed the celite pad with ethyl acetate (20 mL). The filtrate waswashed with water (20 mL), brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to get thecrude product. The crude product was purified by silicagel columnchromatography using 6% methanol in dichloromethane as eluent to obtainthe title compound2-(4-chlorophenoxy)-N-(1-(3-((5-chloropyridin-2-yl)oxy)propyl)piperidin-4-yl)acetamide(0.02 g, 10% yield), as white solid. LCMS (ES) m/z=438.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 1.43-1.49 (m, 2H), 1.64-1.67 (m, 2H),1.81-1.84 (m, 2H), 1.90-1.95 (m, 2H), 2.36 (bs, 2H), 2.78 (d, J=10.0 Hz,2H), 3.57 (bs, 1H), 4.23 (t, J=6.0 Hz, 2H), 4.43 (s, 2H), 6.83 (d, J=8.8Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.74-7.77 (m,1H), 7.90 (d, J=7.6 Hz, 1H), 8.16 (s, 1H).

The Compound of Example 21 was prepared generally according to theprocedure described above for Example 20.

TABLE 8 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 20

2-(4- chlorophenoxy)- N-(1-(3-((5- chloropyridin-2- yl)oxy)propyl)piperidin-4- yl)acetamide 438.1 1.43-1.49 (m, 2 H), 1.64- 1.67 (m, 2 H),1.81-1.84 (m, 2 H), 1.90-1.95 (m, 2 H), 2.36 (bs, 2 H), 2.78 (d, J =10.0 Hz, 2 H), 3.57 (bs, 1 H), 4.23 (t, J = 6.0 Hz, 2 H), 4.43 (s, 2 H),6.83 (d, J = 8.8 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.31 (d, J = 8.4Hz, 2 H), 7.74-7.77 (m, 1 H), 7.90 (d, J = 7.6 Hz, 1 H), 8.16 (s, 1 H).21

2-(4- chlorophenoxy)- N-(1-(3-(3,4- dichlorophenoxy) propyl)piperidin-4-yl)acetamide 471.1 1.41-1.49 (m, 2 H), 1.66 (d, J = 10.8 Hz, 2 H),1.80-1.84 (m, 2 H), 1.94 (t, J = 11.0 Hz, 2 H), 2.36 (t, J = 6.8 Hz, 2H), 2.78 (d, J = 10.8 Hz, 2 H), 3.58- 3.59 (m, 1 H), 4.00 (t, J = 6.0Hz, 2 H), 4.43 (s, 2 H), 6.91- 6.96 (m, 3 H), 7.19 (d, J = 2.4 Hz, 1 H),7.31 (d, J = 8.8 Hz, 2 H), 7.48 (d, J = 8.8 Hz, 1 H), δ 7.89 (d, J = 8.0Hz, 1 H).

Example 224-(2-((4-chlorophenoxy)methyl)-1H-imidazol-1-yl)-1-(3-(4-chlorophenoxy)propyl)piperidine

Step 1:

To a mixture of 4-chlorophenol (5.0 g, 38.892 mmol, 1.0 equiv) inN,N-dimethylmethanamide (10 mL) was added potassium carbonate (10.74 g,138.2 mmol, 3.5 equiv), sodium iodide (0.58 g, 3.889 mmol, 0.1 equiv)and 2-bromo-1,1-dimethoxyethane (6.8 mL, 58.338 mmol, 1.5 equiv) at 27°C. The resulting mixture was heated to 120° C. and stirred for 40 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, the reaction mixture was diluted with water (100 mL), theproduct was extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with cold water (50 mL), brine (50 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to get the crude product. The crude product was purified bysilicagel column chromatography using 20% ethyl acetate in hexane aseluent to obtain the title compound1-chloro-4-(2,2-dimethoxyethoxy)benzene (3.2 g, 38% yield) as colourlessoil. ¹H NMR (400 MHz, CDCl3): δ ppm 3.45 (s, 6H), 3.97 (d, J=5.2 Hz,2H), 4.69 (t, J=4.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz,2H).

Step 2:

To a stirred solution of 1-chloro-4-(2,2-dimethoxyethoxy)benzene (3.2 g,14.81 mmol, 1.0 equiv) in acetone (40 mL) was added 2M hydrochloric acid(4 mL). The resulting mixture was heated to 60° C. and stirred for 6 h.The progress of the reaction was monitored by TLC. After completion ofreaction, the reaction mixture was concentrated under reduced pressure,the residue was diluted with water (100 mL), the product was extractedwith ethyl acetate (3×75 mL), and the combined organics were washed withwater (50 mL), brine (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to get the crudeproduct. The crude product was purified by silicagel columnchromatography using 20% ethyl acetate in hexane as eluent to obtain thetitle compounds 2-(4-chlorophenoxy)acetaldehyde (1.8 g, crude) ascolourless oil. ¹H NMR (400 MHz, CDCl3): δ ppm 4.55 (s, 2H), 6.76-6.88(m, 2H), 7.18-7.28 (m, 2H), 9.84 (s, 1H).

Step 3:

To a stirred solution of 1-(3-(4-chlorophenoxy)propyl)piperidin-4-aminehydrochloride (0.3 g, 0.982 mmol, 1.0 equiv),2-(4-chlorophenoxy)acetaldehyde (0.25 g, 1.474 mmol, 1.5 equiv) andglyoxal (40% in water) (0.21 g, 1.474 mmol, 1.5 equiv) in methanol (10mL) was added ammonium acetate (0.12 g, 1.474 mmol, 1.5 equiv). Theresulting mixture was heated to 80° C. and stirred for 24 h. Theprogress of the reaction was monitored by TLC. After completion ofreaction, the reaction mixture was concentrated under reduced pressure.The obtained residue was dissolved with ethyl acetate (250 mL), washedwith water (100 mL), brine (30 mL), derid over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to get the crudeproduct. The crude product was purified by silicagel columnchromatography using 6% methanol in dichloromethane as eluent to get theimpure compound and it was purified by preparative HPLC [HPLC Method:Column: Inertsil ODS 3V (250 mm×4.6 mm×5 mic), mobile phase (A): 0.1%NH₃ in water, mobile phase (B): acetonitrile, flow rate: 1.0 mL/min, T/%B: 0/20, 10/80, 25/90, 27/20, 30/20] to obtain the title compound4-(2-((4-chlorophenoxy)methyl)-1H-imidazol-1-yl)-1-(3-(4-chlorophenoxy)propyl)piperidine(0.035 g, 7.7% yield) as white solid. LCMS (ES) m/z=460.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): δ ppm 1.96 (bs, 6H), 2.09-2.12 (m, 2H), 2.54-2.57 (m,2H), 3.07 (d, J=10.4 Hz, 2H), 3.99 (bs, 2H), 4.12-4.14 (m, 1H), 5.15 (s,2H), 6.82 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 7.35 (d, J=4.8 Hz,2H), 7.21-7.25 (m, 4H).

TABLE 9 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃)22

4-(2-((4- chlorophenoxy) methyl)-1H- imidazol-1-yl)- 1-(3-(4-chlorophenoxy) propyl)piperidine 460.1 1.96 (bs, 6 H), 2.09-2.12 (m, 2H), 2.54-2.57 (m, 2 H), 3.07 (d, J = 10.4 Hz, 2 H), 3.99 (bs, 2 H),4.12- 4.14 (m, 1 H), 5.15 (s, 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 6.95 (d,J = 8.8 Hz, 2 H), 7.35 (d, J = 4.8 Hz, 2 H), 7.21-7.25 (m, 4 H).

Example 232-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)-3-methylpiperidin-4-yl)acetamide

Step 1:

To a stirred solution of tert-butyl (3-methylpiperidin-4-yl)carbamate(0.2 g, 0.933 mmol, 1.0 equiv), 2-(4-chlorophenoxy)acetic acid (0.2 g,1.119 mmol, 1.2 equiv) and triethyl amine (1.04 mL, 7.466 mmol, 8.0equiv) in dichloromethane (10 mL) was added propylphosphonic anhydridesolution (>50 wt. % in ethyl acetate) (1.18 g, 1.866 mmol, 2.0 equiv) at0° C. The resulting mixture was allowed to warm to 25° C. and stirredfor 3 h. The progress of the reaction was monitored by TLC. Aftercompletion of reaction, the reaction mixture was diluted withdichloromethane (100 mL), washed with water (2×30 mL), brine (30 mL),derid over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to get the crude product. The crude product waspurified by silicagel column chromatography using 5% methanol indichloromethane as eluent to obtain the title compound tert-butyl(1-(2-(4-chlorophenoxy)acetyl)-3-methylpiperidin-4-yl)carbamate (0.21 g,80% yield) as off white solid. LCMS (ES) m/z=327.0 [(M+H)⁺-(t-butylgroup)].

Step 2:

To a solution of tert-butyl(1-(2-(4-chlorophenoxy)acetyl)-3-methylpiperidin-4-yl)carbamate (0.21 g,0.548 mmol, 1.0 equiv) in dichloromethane (5 mL) was added 4Mhydrochloric acid in 1, 4-dioxane (5 mL) at 0° C. The reaction mixturewas allowed to warm to 27° C. and stirred for 4 h. The progress of thereaction was monitored by TLC. After completion of reaction, thereaction mixture was concentrated under reduced pressure to get thecrude product. The crude product was triturated with n-pentane to obtainthe title compound1-(4-amino-3-methylpiperidin-1-yl)-2-(4-chlorophenoxy)ethan-1-onehydrochloride (0.23 g, crude) as off white gum, which was taken as suchto next step without further purification. LCMS (ES) m/z=283.1 [M+H]⁺.

Step 3:

To a stirred solution of1-(4-amino-3-methylpiperidin-1-yl)-2-(4-chlorophenoxy)ethan-1-onehydrochloride (0.12 g, 0.375 mmol, 1.0 equiv), 2-(4-chlorophenoxy)aceticacid (0.084 g, 0.451 mmol, 1.2 equiv) and triethyl amine (0.42 mL, 3.006mmol, 8.0 equiv) in dichloromethane (10 mL) was added propylphosphonicanhydride solution (>50 wt. % in ethyl acetate) (0.5 g, 0.751 mmol, 2.0equiv) at 0° C. The resulting mixture was allowed to warm to 25° C. andstirred for 3 h. The progress of the reaction was monitored by TLC.After completion of reaction, the refraction mixture was diluted withdichloromethane (50 mL), washed with water (2×30 mL), brine (30 mL),derid over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to get the crude product. The crude product waspurified by silicagel column chromatography using 6% methanol indichloromethane as eluent to obtain the title compound2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)-3-methylpiperidin-4-yl)acetamide(0.095 g, 59% yield) as pale green solid. LCMS (ES) m/z=451.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ ppm 0.68-0.70, 0.77, 1.31-1.33 (m, 3H),1.57-1.69, 1.89-1.97 (m, 3H), 2.48, 2.65-2.74 (m, 1H), 3.06-3.09, 3.28(m, 1H), 3.49-3.59, 3.73-3.81 (m, 2H), 4.02, 4.48-4.52 (m, 1H),4.48-4.52 (m, 2H), 4.78-4.89 (m, 2H), 6.90-6.96 (m, 4H), 7.28-7.32 (m,4H), 7.92 (bs, 1H). (Due to diasteromeric mixture the peaks were split).VT NMR at 90° C. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.75-0.81 (m, 3H),1.59-1.73 (m, 2H), 1.97 (bs, 1H), 3.33-3.42 (m, 3H), 3.59-3.62 (m, 1H),4.04-4.06 (m, 1H), 4.47-4.51 (m, 2H), 4.72-4.77 (m, 2H), 6.92-6.97 (m,4H), 7.27-7.31 (m, 4H), 7.60-7.67 (m, 1H).

The Compounds of Examples from 24 to 37 were prepared generallyaccording to the procedure described above for Example 23.

TABLE 10 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 23

2-(4- chlorophenoxy)- N-(1-(2-(4- chlorophenoxy) acetyl)-3-methylpiperidin- 4- yl)acetamide 451.1 0.75-0.81 (m, 3 H), 1.59- 1.73(m, 2 H), 1.97 (bs, 1 H), 3.33-3.42 (m, 3 H), 3.59- 3.62 (m, 1 H),4.04-4.06 (m, 1 H), 4.47-4.51 (m, 2 H), 4.72-4.77 (m, 2 H), 6.92- 6.97(m, 4 H), 7.27-7.31 (m, 4 H), 7.60-7.67 (m, 1 H). 24

N-(4- chloropheneth- yl)-1-(2-(4- chlorophenoxy) acetyl)piperidine- 4-carboxamide 435.1 1.31-1.33 (m, 1 H), 1.49- 1.54 (m, 1 H), 1.61 (bs, 2H), 2.27-2.33 (m, 1 H), 2.57- 2.60 (m, 1 H), 2.66-2.69 (m, 2 H),2.96-3.02 (m, 1 H), 3.21-3.24 (m, 2 H), 3.76- 3.79 (m, 1 H), 4.21-4.24(m, 1 H), 4.74-4.84 (m, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 7.19 (d, J =8.4 Hz, 2 H), 7.30 (t, J = 8.0 Hz, 4 H), 7.78-7.86 (m, 1 H). 25

2-(4- chloropenoxy)- N-(1-(3-(4- chlorophenoxy) propanyl) piperidin-4-yl)acetamide 451 1.28-1.34 (m, 1 H), 1.38- 1.41 (m, 1 H), 1.68-1.76 (m,2 H), 2.65-2.78 (m, 3 H), 3.07-3.13 (m, 1 H), 3.84- 3.87 (m, 2 H),4.15-4.17 (m, 2 H), 4.26-4.27 (m, 1 H), 4.45 (s, 2 H), 6.93 (t, J = 9.2Hz, 4 H), 7.30 (t, J = 12 Hz, 4 H), 7.98-8.00 (m, 1 H). 26

2-(4- chlorophenoxy)- N-(1-(4-(4- chlorophenyl) butanoyl)-3-fluoropiperidin- 4- yl)acetamide 467.3 1.33-1.50 (m, 1 H), 1.72- 1.78(m, 3 H), 2.31-2.33 (m, 2 H), 2.56 (t, J = 7.4 Hz, 2H), 2.85-2.95 (m, 1H), 3.08- 3.17 (m, 0.6 H), 3.20-3.25 (m, 0.4 H), 3.65-3.72 (m, 0.5 H),3.91-4.12 (m, 2 H), 4.26- 4.33 (m, 0.3 H), 4.40 (brs, 1 H), 4.49 (s, 2H), 6.96 (d, J = 8.8 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.31 (t, J =7.4 Hz, 4 H), 8.17 (d, J = 8.4 Hz, 1 H). 27

2-(4- chlorophenoxy)- N-(1-(2-(4- chlorophenoxy) acetyl)piperidin- 3-yl)acetamide 437.4 1.33-1.37 (m, 0.5 H), 1.50 (s, 1.5 H), 1.69 (s, 1 H),1.79 (s, 1 H), 2.73-2.78 (m, 0.5 H), 2.98-3.12 (m, 1.5 H), 3.58- 3.62(m, 1.5 H), 3.76 (s, 1 H), 4.00-4.02 (m, 0.5 H), 4.41- 4.48 (m, 2 H),4.73-4.85 (m, 2 H), 6.92 (s, 4 H), 7.26-7.30 (m, 4 H), 7.95-7.99 (m, 0.5H), 8.10-8.12 (m, 0.46 H). 28

2-(4- chlorophenoxy)- N-(2-(1-(2- (4- chlorophenoxy) acetyl)piperidin-3- yl)ethyl)aceta- mide 465.1 1.10-1.24 (m, 2 H), 1.26- 1.35 (m, 4 H),1.57-1.60 (m, 1 H), 1.71-1.79 (m, 1 H), 2.58- 2.69 (m, 1 H), 2.99-3.12(2 H), 3.61-3.64 (m, 0.5 H), 3.72-3.75 (m, 0.5 H), 3.98- 4.02 (m, 0.5H), 4.11-4.15 (m, 0.5 H), 4.43-4.46 (m, 2 H), 4.76-4.87 (m, 2 H), 6.90-6.95 (m, 4 H), 7.26-7.31 (m, 4 H), 8.04-8.09 (m, 1 H). 29

N-((1-(2-(4- chlorophenoxy) acetyl)piperidin- 3-yl)methyl)- 2-((6-chloropyridin- 3- yl)oxy)acetamide 452.1 1.21-1.26 (m, 1 H), 1.36- 1.39(m, 0.5 H), 1.52-1.58 (m, 0.5 H), 1.70-1.81 (m, 2 H), 2.38-2.44 (m, 1H), 2.69- 2.80 (m, 1 H), 2.95-3.10 (m, 3 H), 3.62-3.68 (m, 1 H),3.98-4.01 (m, 0.5 H), 4.11- 4.14 (m, 0.5 H), 4.56-4.58 (m, 2 H),4.68-4.84 (m, 2 H), 6.90- 6.91 (m, 2 H), 7.24-7.29 (m, 2 H), 7.39-7.45(m, 2 H), 8.11 (s, 1 H), 8.18 (s, 1 H). 30

2-(4- chlorophenoxy)- N-(1-(2-(4- chlorophenoxy) acetyl)-3-fluoropiperidin- 4- yl)acetamide 455.0 1.40-1.43 (m, 0.5 H), 1.54- 1.56(m, 0.5 H), 1.75-1.88 (m, 1 H), 2.90-2.99 (m, 0.5 H), 3.01 (bs, 0.5 H),3.20-3.37 (m, 1 H), 3.69 (d, J = 12.0 Hz, 0.5 H), 4.01-4.09 (m, 2 H),4.31 (bs, 0.7 H), 4.50-4.58 (m, 2.5 H), 4.63 (bs, 0.3 H), 4.79-4.96 (m,2 H), 6.91-6.97 (m, 4 H), 7.29-7.34 (m, 4 H), 8.22 (d, J = 7.6 Hz, 1 H).31

2-(4- chlorophenoxy)- N-(2-(2-(4- chlorophenoxy) acetyl)-2-azabicyclo[2.2.1] heptan-5- yl)acetamide 449.0 1.40-1.58 (m, 2 H), 1.65-1.72 (m, 1 H), 1.88-2.10 (m, 1 H), 2.41-2.48 (m, 0.5 H), 2.67 (d, J =12.8 Hz, 0.5 H), 2.92 (d, J = 11.2 Hz, 0.25 H), 3.09-3.11 (m, 0.25 H),3.17- 3.27 (m, 1 H), 3.31-3.36 (m, 0.5 H), 3.76 (bs, 0.25 H), 3.89 (bs,0.25 H), 4.10-4.20 (m, 0.5 H), 4.26-4.38 (m, 1 H), 4.42-4.67 (m, 3.5 H),4.72- 4.79 (m, 0.5 H), 6.88-6.95 (m, 4 H), 7.27-7.33 (m, 4 H), 8.06 (d,J = 6.4 Hz, 0.5 H), 8.23-8.28 (m, 0.5 H). 32

2-(4- chlorophenoxy)- N-(1- ((1R,2R)-2-(4- chlorophenoxy) cyclopropane-1- carbonyl) piperidin-4- yl)acetamide (Racemate) 463.4 1.29-1.37 (m, 4H), 1.72 (bs, 2 H), 2.31-2.33 (m, 1 H), 2.65-2.73 (m, 1 H), 3.15- 3.19(m, 1 H), 3.95 (bs, 2 H), 4.09 (d, J = 13.2 Hz, 1 H), 4.26 (bs, 1 H),4.46 (d, J = 8.0 Hz, 2 H), 6.96-6.98 (m, 4 H), 7.31- 7.33 (m, 4 H), 8.01(bs, 1 H). 33

2-(4- chlorophenoxy)- N-(1- ((1R,2S)-2-(4- chlorophenoxy) cylcopropane-1- carbonyl) piperidin-4- yl)acetamide (Racemate) 463.1 1.11-1.17 (m, 1H), 1.27- 1.46 (m, 3 H), 1.61-1.76 (m, 2 H), 2.22-2.28 (m, 1 H), 2.48(bs, 0.5 H), 2.73 (t, J = 9.0 Hz, 0.5 H) 2.97 (t, J = 9.0 Hz, 0.5 H)3.22-3.27 (m, 0.5 H), 3.82 (bs, 1 H), 4.08-4.19 (m, 3 H), 4.46 (s, 2 H),6.94- 7.02 (m, 4 H), 7.32 (d, J = 8.0 Hz, 4 H), 7.95-8.01 (m, 1 H). 34

N-(1-((1S,2R)- 2-(4- chlorobenzyl) cyclopropane- 1-carbonyl) piperi-din-4-yl)-2-(4- chlorophenoxy) acetamide (racemate) 461.1 0.71 (bs, 1H), 0.98 (bs, 1 H), 1.32 (bs, 3 H), 1.65 (bs, 2 H), 1.94 (bs, 1 H), 2.48(bs, 1 H), 2.65-2.67 (m, 2 H), 3.08- 3.11 (m, 1 H), 3.86 (bs, 1 H), 4.06(bs, 1 H), 4.18 (bs, 1 H), 4.45 (s, 2 H), 6.95 (d, J = 8.4 Hz, 2 H),7.27 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 4 H), 7.97 (bs, 1 H). 35

N-(1-((1R,2R)- 2-(4- chlorobenzyl) cyclopropane- 1- carbonyl)piperi-din-4-yl)-2-(4- chlorophenoxy) acetamide (Racemate) 461.4 0.85 (bs, 1H), 0.95 (bs, 1 H), 1.09 (bs, 0.5 H), 1.28-1.47 (m, 3 H), 1.60-1.69 (m,2.5 H), 2.01 (d, J = 5.6 Hz, 1 H), 2.60-26.5 (m, 2 H), 3.16- 3.20 (m, 1H), 3.82 (bs, 1 H), 3.92-3.96 (m, 1 H), 4.22- 4.31 (m, 1 H), 4.45 (s, 2H), 6.96 (bs, 2 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 4 H), 7.89-7.98 (m, 1 H). 36

2-(4- chlorophenoxy)- N-(1-(2-(4- chlorophenyl) cyclopropane- 1-carbonyl)piperi- din-4- yl)acetamide 447.1 1.14-1.19 (m, 1 H), 1.29-1.39 (m, 3 H), 1.69-1.72 (m, 2 H), 2.24-2.31 (m, 2 H), 2.72 (bs, 1 H),3.10-3.19 (m, 1 H), 3.88-3.90 (m, 1 H), 4.10 (bs, 1 H), 4.25 (bs, 1 H),4.44 (s, 2 H), 6.95 (d, J = 8.4 Hz, 2 H), 7.19 (d, J = 8.8 Hz, 2 H),7.31 (t, J = 8.4 Hz, 4 H), 7.95-8.01 (m, 1 H). 37

2-(4- chlorophenoxy)- N-(1-(4-(4- chlorophenyl) butanoyl)piperi- din-4-yl)acetamide 449.1 1.26-1.34 (m, 2 H), 1.66- 1.78 (m, 4 H), 2.28 (t, J =7.2 Hz, 2 H), 2.67-2.54 (m, 3H), 3.04 (t, J = 12.0 Hz, 1 H), 3.75 (d, J= 12.8 Hz, 1 H), 3.85 (d, J = 8.0 Hz, 1 H), 4.26 (d, J = 12.8 Hz, 2 H),4.44 (s, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.2 (d, J = 8.4 Hz, 2 H),7.3-7.33 (m, 4 H), 7.97 (d, J = 8.0 Hz, 1 H).

Example 382-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-methylpiperidin-4-yl)acetamide

Step 1:

To a stirred solution of tert-butyl (3-methylpiperidin-4-yl)carbamate(0.2 g, 0.933 mmol, 1.0 equiv) in N,N-dimethylmethanamide (10 mL) wasadded cesium carbonate (0.45 g, 1.399 mmol, 1.5 equiv), triethyl amine(0.26 mL, 1.866 mmol, 2.0 equiv) and 1-(3-bromopropoxy)-4-chlorobenzene(0.33 g, 1.399 mmol, 1.5 equiv) at 25° C. The resulting mixture wasstirred at 25° C. for 16 h. The progress of the reaction was monitoredby TLC. After completion of reaction, the reaction mixture was dilutedwith water (50 mL), the product was extracted with ethyl acetate (2×50mL). The combined organic layers were washed with cold water (50 mL),brine (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to get the crude product. The crudeproduct was purified by silicagel column chromatography using 4%methanol in dichloromethane as eluent to obtain the title compoundtert-butyl(1-(2-(4-chlorophenoxy)ethyl)-3-methylpiperidin-4-yl)carbamate (0.21 g,61% yield) as off white gum. LCMS (ES) m/z=369.2 [M+H]⁺.

Step 2:

To a solution of tert-butyl(1-(2-(4-chlorophenoxy)ethyl)-3-methylpiperidin-4-yl)carbamate (0.21 g,0.569 mmol, 1.0 equiv) in dichloromethane (5 mL), was added 4Mhydrochloric acid in 1, 4-dioxane (5 mL) at 0° C. The reaction mixturewas allowed to warm to 25° C. and stirred for 4 h. The progress of thereaction was monitored by TLC. After completion of reaction, thereaction mixture was concentrated under reduced pressure to get thecrude product. The crude product was triturated with n-pentane to obtainthe title compound1-(2-(4-chlorophenoxy)ethyl)-3-methylpiperidin-4-amine hydrochloride(0.2 g, crude) as off white gum, which was taken as such to next stepwithout further purification. LCMS (ES) m/z=269.2 [M+H]⁺.

Step 3:

To a stirred solution of1-(2-(4-chlorophenoxy)ethyl)-3-methylpiperidin-4-amine hydrochloride(0.15 g, 0.491 mmol, 1.0 equiv), 2-(4-chlorophenoxy)acetic acid (0.11 g,0.589 mmol, 1.2 equiv) and triethyl amine (0.55 mL, 3.931 mmol, 8.0equiv) in dichloromethane (10 mL) was added propylphosphonic anhydridesolution (>50 wt. % in ethyl acetate) (0.62 g, 0.982 mmol, 2.0 equiv) at0° C. The resulting mixture was allowed to warm to 25° C. and stirredfor 6 h. The progress of the reaction was monitored by TLC. Aftercompletion of reaction, the reaction mixture was diluted withdichloromethane (70 mL), washed with water (2×30 mL), brine (30 mL),derid over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to get the crude product. The crude product waspurified by silicagel column chromatography using 4% methanol indichloromethane as eluent to obtain the title compound2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-methylpiperidin-4-yl)acetamide(0.11 g, 21% crude yield) as colourless gum. LCMS (ES) m/z=437.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.71 (d, J=6.8 Hz, 1H), 0.78 (d, J=6.4Hz, 2H), 1.59, 1.71-1.76, (m, 2.5H, 0.41H), 1.89, 1.99-2.04 (m, 0.75H,0.45H), 2.30-2.36 (m, 2H), 2.64-2.65 (m, 2H), 2.88 (bs, 1H), 3.84 (bs,1H), 4.03 (bs, 2H), 4.46-4.56 (m, 2H), 6.92-6.96 (m, 4H), 7.27-7.32 (m,4H), 7.66-7.68, 7.83-7.85 (m, 0.63H, 0.32H).

The Compounds of Examples 39 to 50 were prepared generally according tothe procedure described above for Example 38.

TABLE 11 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 38

2-(4- chlorophenoxy)- N-(1-(2-(4- chlorophenoxy) ethyl)-3-methylpiperidin- 4-yl)acetamide 437.1 0.71 (d, J = 6.8 Hz, 1 H), 0.78(d, J = 6.4 Hz, 2 H), 1.59, 1.71- 1.76, (m, 2.5 H, 0.41 H), 1.89,1.99-2.04 (m, 0.75 H, 0.45 H), 2.30-2.36 (m, 2 H), 2.64-2.65 (m, 2 H),2.88 (bs, 1 H), 3.84 (bs, 1 H), 4.03 (bs, 2 H), 4.46-4.56 (m, 2 H),6.92- 6.96 (m, 4 H), 7.27-7.32 (m, 4 H), 7.66-7.68, 7.83- 7.85 (m, 0.63H, 0.32 H). 39

N,1-bis(2-(4- chlorophenoxy) ethyl)piperidine- 4- carboxamide 437.11.49-1.58 (m, 4 H), 1.97 (t, J = 10.6 Hz, 2 H), 2.04-2.09 (m, 1 H),2.62-2.64 (m, 2 H), 2.88-2.90 (m, 2 H), 3.34- 3.38 (m, 2 H), 3.94 (t, J= 5.6 Hz, 2 H), 4.02 (t, J = 5.6 Hz, 2 H), 6.93 (d, J = 8.4 Hz, 4 H),7.27-7.30 (m, 4 H), 7.92 (bs, 1 H). 40

N-(2-(4- chlorophenoxy) ethyl)-1-(3-(4- chlorophenoxy) propyl)piperidine-4- carboxamide 451.1 1.51-1.61 (m, 4 H), 1.80- 1.83 (m, 4 H),2.04-2.07 (m, 1 H), 2.30-2.35 (m, 2 H), 2.82-2.84 (m, 2 H), 3.36- 3.37(m, 2 H), 3.92-3.95 (m, 4 H), 6.91-6.94 (m, 4 H), 7.27-7.30 (m, 4 H),7.92 (bs, 1 H). 41

2-(4- chlorophenoxy)- N-(1-(2-(4- chlorophenoxy) ethyl)-3- hydroxy-piperidin-4- yl)acetamide 439 1.39-1.41 (m, 1 H), 1.68- 1.71 (m, 1 H),1.86-1.91 (m, 1 H), 1.98-2.04 (m, 1 H), 2.69 (t, J = 5.4 Hz, 2 H), 2.80-2.82 (m, 1 H), 2.98-3.00 (m, 1 H), 3.43 (bs, 2H), 4.03 (t, J = 5.4 Hz, 2H), 4.44 (s, 2 H), 4.71-4.72 (m, 1 H), 6.95 (t, J = 9.4 Hz, 4 H), 7.30(t, J = 9.0 Hz, 4 H), 7.82-7.83 (m, 1 H). 42

6-chloro-N-(1- (3-(4- chlorophenoxy) propyl) piperidin-4- yl)chromane-2-carboxamide 463.1 1.43-1.52 (m, 2 H), 1.68- 1.72 (m, 2 H), 1.78-1.88 (m,3 H), 1.90-1.99 (m, 2 H), 2.07-2.15 (m, 1 H), 2.33- 2.41 (m, 2 H), 2.67(d, J = 10.4 Hz, 1 H), 2.71-2.82 (m, 3 H), 3.57 (bs, 1 H), 3.96 (d, J =6.0 Hz, 2 H), 4.49 (d, J = 6.8 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 6.93(d, J = 8.0 Hz, 2 H), 7.11 (d, J = 7.6 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1 H). 43

N-(1-(3-(4- chlorophenoxy) propyl) piperidin- 4-yl)-2-((6-chloropyridin-3- yl)oxy) acetamide 440.0 1.40-1.52 (m, 2H), 1.64- 1.72(m, 2 H), 1.79-1.88 (m, 2 H), 1.90-2.00 (m, 2 H), 2.35-2.42 (m, 2 H),2.79 (bs, 2 H), 3.60 (bs, 1 H), 3.97 (s, 2 H), 4.56 (s, 2 H), 6.93 (d, J= 8.4 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2 H), 7.43 (s, 2 H), 7.98 (bs, 1H), 8.11 (bs, 1 H). 44

N-(1-(3-(4- chlorophenoxy) propyl) piperidin- 4-yl)-2-(3,4-dichlorophenoxy) acetamide 473.1 1.41-1.49 (m, 2 H), 1.65- 1.68 (m, 2H), 1.82 (t, J = 6.6 Hz, 2 H), 1.94 (t, J = 10.6 Hz, 2 H), 2.36-2.37 (m,2 H), 2.78 (d, J = 10.8 Hz, 2 H), 3.58- 3.60 (m, 1 H), 3.96 (t, J = 6.2Hz, 2 H), 4.49 (s, 2 H), 6.91- 6.97 (m, 3 H), 7.23 (d, J = 2.4 Hz, 1 H),7.28 (d, J = 8.8 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.93 (d, J = 7.6Hz, 1 H). 45

N-(1-(3-(4- chlorophenoxy) propyl)piperidin- 4-yl)-2-(2,4-dichlorophenoxy) acetamide 473.1 1.38-1.45 (m, 2 H), 1.69- 1.71 (m, 2H), 1.81 (t, J = 6.6 Hz, 2 H), 1.97 (t, J = 10.2 Hz, 2 H), 2.37 (t, J =7.0 Hz, 2 H), 2.73-2.76 (m, 2 H), 3.57- 3.59 (m, 1 H), 3.96 (t, J = 6.4Hz, 2 H), 4.57 (s, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 7.01 (d, J = 8.8 Hz,1 H), 7.28 (d, J = 8.8 Hz, 2 H), 7.33-7.35 (m, 1 H), 7.56 (d, J = 2.0Hz, 1 H), 7.82 (d, J = 7.6 Hz, 1 H). 46

2-(4- chlorophenoxy)- N-((1R,5S)-8- (3-(4- chlorophenoxy) propyl)-8-azabicyclo[3.2.1] octan-3- yl)acetamide 463.3 1.49-1.58 (m, 6H), 1.77-1.83 (m, 4 H), 2.42-2.48 (m, 2 H), 3.17 (s, 2 H), 4.01 (t, J = 6.2 Hz, 3H), 4.39 (s, 2 H), 6.91-6.94 (m, 4 H), 7.29 (t, J = 7.8 Hz, 4 H), 7.86(d, J = 8.4 Hz, 1 H). 47

2-(4- chlorophenoxy)- N-(1-(2-(3,4- dichlorophenoxy) ethyl)-3-fluoropiperidin- 4-yl)acetamide 475.1 1.45-1.53 (m, 1 H), 1.70 (bs, 1H), 2.11-2.19 (m, 2 H), 2.75 (bs, 2H), 2.81 (d, J = 11.2 Hz, 1 H),3.20-3.25 (m, 1 H), 3.72-3.85 (m, 1 H), 4.09 (t, J = 5.2 Hz, 2 H), 4.38-4.43 (m, 0.5 H), 4.47 (s, 2 H), 4.52-4.57 (m, 0.5 H), 6.93- 6.97 (m, 3H), 7.23 (d, J = 2.0 Hz, 1 H), 7.32 (d, J = 8.8 Hz, 2 H), 7.48 (d, J =8.8 Hz, 1 H), 8.17 (d, J = 8.4 Hz, 1 H). 48

N-(1-(2-(4- chlorophenoxy) ethyl)-3- fluoropiperidin- 4-yl)-2-(3,4-dichlorophenoxy) acetamide 477.1 1.45-1.53 (m, 1 H), 1.71 (bs, 1 H),2.11-2.17 (m, 2 H), 2.75 (s, 2 H), 2.82 (d, J = 10.8 Hz, 1 H), 3.20-3.25(m, 1 H), 3.78 (bs, 1 H), 4.05 (t, J = 5.6 Hz, 2 H), 4.40-4.41 (m, 0.5H), 4.53 (s, 2.5 H), 6.93-6.99 (m, 3 H), 7.23 (d, J = 2.8 Hz, 1 H), 7.29(d, J = 9.2 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 1 H), 8.18 (d, J = 8.8 Hz, 1H). 49

2-(4- chlorophenoxy)- N-((1-(3-(4- chlorophenoxy) propyl)piperidin-4-yl)methyl) acetamide 451.1 1.11-1.20 (m, 2 H), 1.31 (bs, 1 H), 1.55(bs, 2H), 1.83- 2.15 (m, 4 H), 2.35-2.48 (m, 2 H), 2.75-2.81 (m, 2H),2.99 (bs, 2 H), 3.97 (s, 2H), 4.46 (s, 2H), 6.93 (t, J = 10 Hz, 4 H),7.30 (t, J = 9.2 Hz, 4 H), 8.06 (bs, 1 H). 50

2-(4- chlorophenoxy)- N-(1-(2-(4- chlorophenoxy) ethyl)-3-fluoropiperidin- 4-yl)acetamide 442.1 1.45-1.54 (m, 1 H), 1.65- 1.75 (m,1 H), 2.11-2.19 (m, 2 H), 2.76 (t, J = 5.6 Hz, 2 H), 2.81 (d, J = 11.2Hz, 1 H), 3.21- 3.27 (m, 1 H), 3.75-3.85 (m, 1 H), 4.05 (t, J = 5.2 Hz,2 H), 4.39-4.44 (m, 0.5 H), 4.47 (s, 2 H), 4.51-4.57 (m, 0.5 H), 6.95(t, J = 8.4 Hz, 4 H), 7.28- 7.33 (m, 4 H), 8.16 (d, J = 8.4 Hz, 1 H).

Example 514-(4-chlorophenoxy)-2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)butanoicacid hydrochloride

Step 1:

To a solution of 4-chlorophenol (2.0 g, 15.556 mmol, 1 equiv) inacetonitrile (60 mL) was added anhydrous potassium carbonate (4.3 g,31.113 mmol, 2 equiv) and ethyl 4-bromobutanoate (3.56 mL, 24.891 mmol,1.6 equiv). The reaction mixture was heated to reflux and stirred for 8h. The progress of the reaction was monitored by TLC. After completionof reaction, the reaction mixture was allowed to cool to 27° C.,filtered the solid and washed with ethyl acetate (100 mL). The filtratewas concentrated under reduced pressure to give the crude product. Thecrude product was purified by silica gel column chromatography using 10%ethyl acetate in hexane as eluent to obtain the title compound ethyl4-(4-chlorophenoxy)butanoate (3.5 g, 92% yield) as colourless liquid.LCMS (ES) m/z=242.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl3): δ ppm 1.25 (t,J=6.8 Hz, 3H), 2.06-2.06 (m, 2H), 2.49 (t, J=6.8 Hz, 2H), 3.97 (t, J=6.0Hz, 2H), 4.11-4.17 (m, 2H), 6.80 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.8 Hz,2H).

Step 2:

To a solution of ethyl 4-(4-chlorophenoxy)butanoate (1.0 g, 4.120 mmol,1.0 equiv) in dry tetrahydrofuran (10 mL) was added lithiumdiisopropylamide solution (2.0 M in THF/heptane/ethylbenzene) (2.47 mL,4.944 mmol, 1.2 equiv) slowly at −78° C. The reaction mixture wasstirred for another 1 h at −78° C. After 1 h, a solution of carbontetrabromide (2.0 g, 6.198 mmol, 1.5 equiv) in dry tetrahydrofuran (15mL) was added at −78° C., the mixture was gradually allowed to warm to27° C. and stirred for 2 h. The mixture was quenched with saturatedaqueous solution of ammonium chloride (20 mL) and extracted with ethylacetate (3×100 mL). The combined organics were dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure togive the crude product. The crude product was purified by silica gelcolumn chromatography using 10% ethyl acetate in hexane as eluent toobtain the title compound ethyl 2-bromo-4-(4-chlorophenoxy)butanoate(0.45 g, crude) as pale brown liquid. ¹H NMR (400 MHz, CDCl3): δ ppm1.30 (t, J=7.2 Hz, 3H), 2.35-2.43 (m, 1H), 2.52-2.60 (m, 1H), 4.04-4.13(m, 2H), 4.22-4.27 (m, 2H), 4.52-4.55 (m, 1H), 6.81 (d, J=8.8 Hz, 2H),7.23 (d, J=8.8 Hz, 2H).

Step 3:

To a solution of ethyl 2-bromo-4-(4-chlorophenoxy)butanoate (0.16 g,0.491 mmol, 1 equiv) in N,N-dimethylformamide (10 mL) were added a2-(4-chlorophenoxy)-N-(piperidin-4-yl)acetamide hydrochloride (0.15 g,0.491 mmol, 1 equiv), cesium carbonate (0.32 g, 0.982 mmol, 2.0 equiv)and triethyl amine (0.14 mL, 0.982 mmol, 2.0 equiv). The resultingmixture was stirred for 16 h at 27° C. The progress of the reaction wasmonitored by TLC. After completion of reaction, the reaction mixture wasquenched with water (50 mL) and extracted with ethyl acetate (3×30 mL),the combined organics were washed with water (30 mL), brine (20 mL),dried over anhydrous sodium sulphate, filtered and concentrated underreduced pressure to get the crude product. The crude product waspurified by silica gel column chromatography (Combiflash) using 50%ethyl acetate in hexane as eluent. The product was again purified withpreparative HPLC (analytical Conditions: column: inertsil ODS 3V (250mm×4.6 mm×5 mic), mobile phase (A): 0.1% Ammonia in w ater, mobile phase(B): acetonitrile, flow rate: 1.0 mL/min, T/% B: 0/20, 10/80, 25/90,27/20, 30/20) to obtain the title compound ethyl4-(4-chlorophenoxy)-2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)butanoate(0.08 g, 40% yield) as off white solid. LCMS (ES) m/z=509.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.21-1.31 (m, 3H), 1.31-1.47 (m, 3H), 1.66(bs, 2H), 1.96-2.18 (m, 2H), 2.24-2.28 (m, 1H), 2.73 (d, J=11.2 Hz, 1H),2.82 (d, J=11.6 Hz, 1H), 3.38 (t, J=6.8 Hz, 1H) 3.55-3.57 (m, 1H),3.93-4.13 (m, 4H), 4.42 (s, 2H), 6.90-6.95 (m, 4H), 7.28-7.32 (m, 4H),7.90 (d, J=8.0 Hz, 1H).

Step 4:

To a solution of ethyl4-(4-chlorophenoxy)-2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)butanoate(0.04 g, 0.078 mmol, 1 equiv) in ethanol (5 mL) was added sodiumhydroxide (0.3 g, 0.785 mmol, 10 equiv) in 1 ml of water, the resultingmixture was heated to 50° C. and stirred for 4 h. The progress of thereaction was monitored by TLC. After completion of reaction, the ethanolwas removed by evaporation, the residue was diluted with water (2 mL),acidified with 1.5 M hydrochloric acid to pH˜3 to 4. The aqueous wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with water (10 mL), dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to give the crudeproduct.

The crude product triturated with n-pentane and dried to obtain thetitle compound4-(4-chlorophenoxy)-2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)butanoicacid (0.025 g, 67% yield) as off white solid. LCMS (ES) m/z=481.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.41-1.47 (m, 2H), 1.94 (bs,2H), 2.05-2.19 (m, 2H), 2.25-2.30 (m, 1H), 2.56-2.59 (m, 1H), 2.75-2.78(m, 1H), 2.83-2.86 (m, 1H), 3.32-3.34 (m, 1H), 3.57 (bs, 1H), 3.95-3.99(m, 1H), 4.02-4.05 (m, 1H), 4.42 (s, 2H), 6.91-6.95 (m, 4H), 7.28-7.32(m, 4H), 7.93 (d, J=8.0 Hz, 1H).

Step 5:

To mixture of4-(4-chlorophenoxy)-2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)butanoicacid (0.02 g, 0.041 mmol, 1 equiv) in tetrahydrofuran (1 mL) was added 1M aqueous hydrochloric acid (2 mL) at 27° C. and the resulting mixturewas stirred for 10 min (up to clear solution). The reaction mixture wasconcentrated under reduced pressure to get the crude product, which wastriturated with n-pentane and dried to obtain the title compound4-(4-chlorophenoxy)-2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)butanoicacid hydrochloride (0.015 g, 71% yield) as off white solid. LCMS (ES)m/z=481.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.79 (bs, 2H), 1.91(bs, 2H), 2.25 (bs, 1H), 3.20 (bs, 2H), 3.86 (bs, 1H), 4.04-4.12 (m,3H), 4.47 (s, 2H), 6.92-6.96 (m, 4H), 7.32 (d, J=7.6 Hz, 4H), 8.19 (d,J=6.8 Hz, 1H), 10.2 (bs, 1H). (Note: Protons are merged with waterresidual peak). ¹H NMR-D20 (400 MHz, DMSO-d₆) δ ppm 1.76-1.84 (m, 2H),1.94 (bs, 2H), 2.23-2.30 (m, 1H), 2.39 (bs, 1H), 3.09-3.14 (m, 1H),3.20-3.25 (m, 1H), 3.35-3.38 (m, 1H), 3.49-3.52 (m, 1H), 3.84-3.86 (m,1H), 4.00-4.10 (m, 3H), 4.45 (s, 2H), 6.90-6.95 (m, 4H), 7.29 (d, J=8.4Hz, 4H).

TABLE 12 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 51

4-(4- chlorophenoxy)- 2-(4-(2-(4- chlorophenoxy) acetamido) piperidin-1-yl)butanoic acid hydrochloride 481.1 1.76-1.84 (m, 2 H), 1.94 (bs, 2 H),2.23-2.30 (m, 1 H), 2.39 (bs, 1 H), 3.09-3.14 (m, 1 H), 3.20-3.25 (m, 1H), 3.35-3.38 (m, 1 H), 3.49- 3.52 (m, 1 H), 3.84-3.86 (m, 1 H),4.00-4.10 (m, 3 H), 4.45 (s, 2 H), 6.90-6.95 (m, 4 H), 7.29 (d, J = 8.4Hz, 4 H).

Example 522-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)-2-oxopiperidin-4-yl)acetamide

Step 1:

To a solution of 1-(3-bromopropoxy)-4-chlorobenzene (1.0 g, 6.509 mmol,1 equiv) in dichloromethane (15 mL) were added ethyl 3-aminopropanoatehydrochloride (1.62 g, 6.509 mmol, 1.0 equiv) and triethyl amine (1.82mL, 13.019 mmol, 2.0 equiv). The resuting mixture was subjected tomicrowave irradiation at 80° C. for 1 h. The progress of the reactionwas monitored by TLC. After completion of reaction, the reaction mixturewas diluted with dichloromethane (100 mL), washed with water (2×30 mL),brine (30 mL), dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to get the crude product. The crudeproduct was purified by silicagel column chromatography using 4%methanol in dichloromethane as eluent to obtain the title compound ethyl3-((3-(4-chlorophenoxy)propyl)amino)propanoate (0.3 g, crude) as palebrown gum. LCMS (ES) m/z=286.1 [M+H]⁺

Step 2:

To a solution of ethyl 3-((3-(4-chlorophenoxy)propyl)amino)propanoate(0.8 g, 2.799 mmol, 1.0 equiv) in dichloromethane (20 mL) were addedethyl 3-chloro-3-oxopropanoate (0.36 mL, 2.799 mmol, 1.0 equiv) andtriethylamine (0.78 mL, 5.598 mmol, 2.0 equiv) at 0° C. The resutingmixture was allowed to warm to 27° C. and stirred for 2 h. The progressof the reaction was monitored by TLC. After completion of reaction, thereaction mixture was diluted with dichloromethane (100 mL), washed withwater (2×30 mL), brine (30 mL), dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to get the crudeproduct. The crude product was purified by silicagel columnchromatography using 70% ethyl acetate in hexane as eluent to obtain thetitle compound ethyl3-((3-(4-chlorophenoxy)propyl)(3-ethoxy-3-oxopropyl)amino)-3-oxopropanoate(1.1 g, crude) as pale brown liquid. LCMS (ES) m/z=400.1 [M+H]⁺

Step 3:

To a stirred solution of ethyl3-((3-(4-chlorophenoxy)propyl)(3-ethoxy-3-oxopropyl)amino)-3-oxopropanoate(1.1 g crude, 2.750 mmol, 1.1 equiv) was added sodium ethoxide solution(21% in ethanol) (1.016 mL, 3.301 mmol, 1.2 equiv) at 0° C. The reactionmixture was allowed to warm to 27° C. and stirred for 16 h. The reactionmixture was concentrated under reduced pressure; the residue wastriturated with n-pentane and diethyl ether to obtain solid crudeintermediate. The obtained solid was dissolved with dichloromethane (10mL) and 2M hydrochloric acid (20 mL) and stirred for 30 minutes at 27°C. The organic phases were separated out and the aqueous layer wasextracted with dichloromethane (20 mL). The combined organics were driedover anhydrous sodium sulphate, filtered and concentrated under reducedpressure to give the crude intermediate. The crude intermediate wasdissolved with acetonitrile (10 mL) and water (0.5 mL) and the mixturewas heated to 70° C. and stirred for 1 h. After 1 h, the reactionmixture was concentrated under reduced pressure to obtain the crudeproduct, which was purified by silicagel column chromatography using 50%ethyl acetate in hexane as eluent to obtain the title compound1-(3-(4-chlorophenoxy)propyl)piperidine-2,4-dione (0.2 g) as off whitegum. LCMS (ES) m/z=282.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl3): δ ppm2.04-2.11 (m, 2H), 2.60-2.65 (m, 2H), 3.34 (s, 2H), 3.58-3.63 (m, 2H),3.65-3.70 (m, 2H), 3.98 (t, J=6.4 Hz, 2H), 6.79-6.82 (m, 2H), 7.23 (d,J=9.6 Hz, 2H).

Step 4:

To a stirred solution of1-(3-(4-chlorophenoxy)propyl)piperidine-2,4-dione (0.09 g, 0.319, 1.0equiv) in methanol (5 mL) was added sodium borohydride (0.12 g, 3.194mmol, 10 equiv) at 26° C. The progress of the reaction was monitored byTLC. The reaction was quenched with cold water (10 mL), the product wasextracted by ethyl acetate (3×30 mL). The combined organics were washedwith brine (30 mL), dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to give the crude product. The crudeproduct was purified by silicagel column chromatography using 5%methanol in dichloromethane as eluent to obtain the title compound1-(3-(4-chlorophenoxy)propyl)-4-hydroxypiperidin-2-one (0.08 g, crude)as pale brown gum. LCMS (ES) m/z=284.1 [M+H]⁺

Step 5:

To a stirred mixture of1-(3-(4-chlorophenoxy)propyl)-4-hydroxypiperidin-2-one (0.085 g crude,0.299 mmol, 1.0 equiv), 4-dimethylaminopyridine (0.11 g, 0.898 mmol, 3.0equiv) in dichloromethane (5 mL) was added methane sulfonylchloride(0.07 mL, 0.898 mmol, 3.0 equiv) at 0° C. The reaction mixture washeated slowly to 50° C. and stirred for 12 h. The progress of thereaction was monitored by TLC. The reaction mixture was allowed to coolto 26° C., diluted with dichloromethane (50 mL), washed with water (2×30mL), brine (20 mL), dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to give the crude product. The crudeproduct was purified by silicagel column chromatography using 10%methanol in dichloromethane as eluent to obtain the title compound1-(3-(4-chlorophenoxy)propyl)-2-oxopiperidin-4-yl methanesulfonate (0.08g, crude) as pale brown oil. LCMS (ES) m/z=362.1 [M+H]+

Step 6:

In autoclave, a mixture of1-(3-(4-chlorophenoxy)propyl)-2-oxopiperidin-4-yl methanesulfonate(0.085 g crude, 0.234 mmol, 1.0 equiv) and methanolic ammonia (10 mL)were heated to 65° C. and stirred for 12 h. After 12 h, the reaction wasallowed to cool to 27° C. and reaction mixture was concentrated underreduced pressure to obtain the crude product4-amino-1-(3-(4-chlorophenoxy)propyl)piperidin-2-one (0.1 g, crude) asbrown oil. The crude product was taken as such next step withoutpurification. LCMS (ES) m/z=283.1 [M+H]⁺

Step 7:

To a mixture of 4-amino-1-(3-(4-chlorophenoxy)propyl)piperidin-2-one(0.1 g crude, 0.353 mmol, 1.0 equiv), 2-(4-chlorophenoxy)acetic acid(0.065 g, 0.353 mmol, 1.0 equiv) and triethyl amine (0.25 mL, 1.768mmol, 5.0 equiv) in dichloromethane (10 mL) was added T3P (50 wt. % inethyl acetate) (0.44 mL, 0.707 mmol, 2.0 equiv) at 0° C. The reactionmixture was allowed to warm to 27° C., stirred for 16 h. The progress ofthe reaction was monitored by TLC. After completion of reaction, thereaction mixture was diluted with dichloromethane (30 mL), washed withwater (30 mL), brine (25 mL), dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to give the crudeproduct. The crude product was purified by silica gel columnchromatography (Combiflash) using 6% methanol in dichloromethane aseluent to obtain the title compound2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)-2-oxopiperidin-4-yl)acetamide(0.0031 g) as pale brown gum. LCMS (ES) m/z=451.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ ppm 1.64 (m, 1H), 1.80-2.03 (m, 2H), 2.16-2.23 (m, 1H),2.27-2.33 (m, 1H), 2.73-2.78 (m, 1H), 3.30-3.38 (m, 1H), 3.40-3.45 (m,1H), 3.55 (t, J=14.4 Hz, 2H), 3.98 (t, J=12 Hz, 2H), 4.32 (bs, 1H), 4.45(s, 2H), 6.43 (d, J=7.6 Hz, 1H), 6.79-6.85 (m, 4H), 7.20-7.28 (m, 4H).

TABLE 13 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃)52

2-(4- chlorophenoxy)- N-(1-(3-(4- chlorophenoxy) propyl)-2-oxopiperidin- 4- yl)acetamide 451.1 1.64 (m, 1 H), 1.80-2.03 (m, 2 H),2.16-2.23 (m, 1 H), 2.27-2.33 (m, 1 H), 2.73-2.78 (m, 1 H), 3.30- 3.38(m, 1 H), 3.40- 3.45 (m, 1 H), 3.55 (t, J = 14.4 Hz, 2 H), 3.98 (t, J =12 Hz, 2 H), 4.32 (bs, 1 H), 4.45 (s, 2 H), 6.43 (d, J = 7.6 Hz, 1 H),6.79-6.85 (m, 4 H), 7.20-7.28 (m, 4 H).

Example 534-(4-chlorophenoxy)-2-(4-(2-(3,4-dichlorophenoxy)acetamido)piperidin-1-yl)butanoicacid hydrochloride

Step 1:

To a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (0.25 g,1.248 mmol, 1 equiv), 2-(3,4-dichlorophenoxy)acetic acid (0.3 g, 1.373mmol, 1.1 equiv) and triethyl amine (1.4 mL, 9.986 mmol, 8.0 equiv) indichloromethane (10 mL) was added T3P (50 wt. % in ethyl acetate) (1.58mL, 2.496 mmol, 2.0 equiv) at 0° C. The reaction mixture was allowed towarm to 27° C. and stirred for 12 h. The progress of the reaction wasmonitored by TLC. After completion of reaction, the reaction mixture wasdiluted with dichloromethane (50 mL), washed with water (2×30 mL), brine(30 mL), dried over anhydrous sodium sulphate, filtered and concentratedunder reduced pressure to give the crude product. The crude product waspurified by silicagel column chromatography (Combiflash) using 5%methanol in dichloromethane as eluent to obtain the title compoundtert-butyl 4-(2-(3,4-dichlorophenoxy)acetamido)piperidine-1-carboxylate(0.42 g, 84% yield) as off white gum. LCMS (ES) m/z=303.1 [(M+H)-(Bocgroup)]⁺. ¹H NMR (400 MHz, CDCl3): δ ppm 1.35-1.38 (m, 2H), 1.45 (s,9H), 1.90-1.93 (m, 2H), 2.87 (bs, 2H), 4.03-4.04 (m, 3H), 4.44 (s, 2H),6.30 (d, J=7.6 Hz, 1H), 6.76-6.79 (m, 1H), 7.04 (d, J=2.4 Hz, 1H), 7.37(d, J=8.8 Hz, 1H).

Step 2:

To a solution of tert-butyl4-(2-(3,4-dichlorophenoxy)acetamido)piperidine-1-carboxylate (0.42 g,1.044 mmol, 1 equiv) in dichloromethane (5 mL) was added 4M hydrochloricacid solution in 1, 4-dioxane (5 mL) at 0° C. The resulting mixture wasallowed to warm to 27° C. and stirred for 4 h. The progress of thereaction was monitored by TLC. After completion of reaction, the mixturewas concentrated under reduced pressure to obtain the title compound2-(3,4-dichlorophenoxy)-N-(piperidin-4-yl)acetamide hydrochloride (0.38g, crude) as off white solid. LCMS (ES) m/z=303.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ ppm 1.63-1.66 (m, 2H), 1.84-1.87 (m, 2H), 2.94 (bs,2H), 3.22 (s, 2H), 3.89 (bs, 1H), 4.53 (s, 2H), 6.94-6.97 (m, 1H), 7.22(d, J=2.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H),8.62-8.70 (m, 2H), 11.0 (bs 1H). The crude product was taken as such tonext step without purification.

Step 3:

To a solution of 2-(3,4-dichlorophenoxy)-N-(piperidin-4-yl)acetamidehydrochloride (0.2 g, 0.588 mmol, 1 equiv) in dichloromethane (10 mL)were added ethyl 2-bromo-4-(4-chlorophenoxy)butanoate (0.22 g, 0.706mmol, 1.2 equiv) and triethyl amine (0.25 mL, 1.766 mmol, 3.0 equiv).The resulting mixture was subjected to microwave irradiation at 80° C.for 2 h. The progress of the reaction was monitored by TLC. Aftercompletion of reaction, the reaction mixture was diluted with ethylacetate (100 mL), washed with water (2×30 mL), brine (30 mL), dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to give the crude product. The crude product was purified byflash column chromatography (Combiflash) using a silica gel column andthe product was eluted at 5% methanol in dichloromethane as eluent toobtain the title compound ethyl4-(4-chlorophenoxy)-2-(4-(2-(3,4-dichlorophenoxy)acetamido)piperidin-1-yl)butanoate(0.07 g) as pale brown gum. LCMS (ES) m/z=543.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl3): δ ppm 1.25-1.29 (m, 3H), 1.42 (bs, 2H), 1.92 (bs, 2H), 2.06 (bs,1H), 2.16 (bs, 1H), 2.34 (bs, 1H), 2.69-2.89 (m, 3H), 3.47 (bs, 1H),3.88-3.96 (m, 2H), 4.04 (bs, 1H), 4.18 (bs, 2H), 4.42 (s, 2H), 6.30 (bs,1H), 6.76-6.81 (m, 3H), 7.04 (bs, 1H), 7.21-7.25 (m, 3H), 7.37 (d, J=8.0Hz, 1H).

Step 4:

To a solution of ethyl4-(4-chlorophenoxy)-2-(4-(2-(3,4-dichlorophenoxy)acetamido)piperidin-1-yl)butanoate(0.07 g, 0.128 mmol, 1 equiv) in ethanol (5 mL) was added sodiumhydroxide (0.05 g, 1.287 mmol, 10 equiv) in 2 ml of water, the mixturestirred for 4 h. The progress of the reaction was monitored by TLC.After completion of reaction, the ethanol was removed by evaporation,the residue was diluted with water (5 mL), acidified with 1.5Mhydrochloric acid to pH 2 to 3. The aqueous layer was extracted withethyl acetate (3×30 mL). The combined organic layers were washed withwater (10 mL), dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to give the crude product. Which wastriturated with diethyl ether and n-pentane to obtain the title compound4-(4-chlorophenoxy)-2-(4-(2-(3,4-dichlorophenoxy)acetamido)piperidin-1-yl)butanoicacid (0.048 g, 72% yield) as off white solid. LCMS (ES) m/z=515.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.68 (bs, 2H), 1.84 (bs, 2H),2.20 (bs, 2H), 2.91 (bs, 2H), 3.77 (bs, 2H), 4.03 (bs, 1H), 4.08 (bs,1H), 4.52 (s, 2H), 6.92-6.97 (m, 3H), 7.22 (d, J=2.8 Hz, 1H), 7.32 (d,J=8.8 Hz, 2H), 7.49-7.52 (m, 1H), 8.14 (bs, 1H). (two protons are mergedwith water peak. ¹H NMR-D20 (400 MHz, DMSO-d₆): δ ppm 1.76-1.79 (m, 2H),1.93-1.97 (m, 2H), 2.24-2.32 (m, 2H), 3.01-3.11 (m, 2H), 3.30-3.33 (m,1H), 3.38-3.42 (m, 1H), 3.83 (bs, 2H), 4.08-4.12 (m, 2H), 4.54 (s, 2H),6.95-7.00 (m, 3H), 7.24 (bs, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.8Hz, 1H).

Step 5:

To a mixture of4-(4-chlorophenoxy)-2-(4-(2-(3,4-dichlorophenoxy)acetamido)piperidin-1-yl)butanoicacid (0.045 g, 0.087 mmol, 1 equiv) in tetrahydrofuran (2 mL) was added1 M aqueous hydrochloric acid (2 mL) at 27° C. and the resulting mixturewas stirred for 10 min (up to clear solution). The reaction mixture wasconcentrated under reduced pressure to give the crude product, which wastriturated with n-pentane and dried to obtain the title compound4-(4-chlorophenoxy)-2-(4-(2-(3,4-dichlorophenoxy)acetamido)piperidin-1-yl)butanoicacid hydrochloride (0.045 g, 95% yield) as off white solid. LCMS (ES)m/z=515.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.81-1.83 (m, 2H),1.93 (bs, 2H), 2.26-2.27 (m, 1H), 3.13 (bs, 2H), 3.50 (bs, 2H), 3.87(bs, 1H), 4.05 (bs, 2H), 4.10-4.14 (m, 1H), 4.54 (s, 2H), 6.93-6.97 (m,3H), 7.22 (d, J=3.2 Hz, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz,1H). 8.27 (d, J=7.2 Hz, 1H). 10.3 (bs, 1H). (Note: Protons are mergedwith water residual peak). ¹H NMR-D20 (400 MHz, DMSO-d₆) δ ppm 1.76-1.81(m, 2H), 1.93 (bs, 2H), 2.23-2.27 (m, 1H), 2.36 (bs, 1H), 3.06-3.12 (m,1H), 3.15-3.21 (m, 1H), 3.32-3.35 (m, 1H), 3.49-3.71 (m, 1H), 3.82 (bs,1H), 3.95-3.97 (m, 1H), 4.02-4.10 (m, 2H), 4.49 (s, 2H), 6.90-6.95 (m,3H), 7.19 (d, J=2.4 Hz, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz,1H).

TABLE 14 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 53

4-(4- chlorophenoxy)- 2-(4-(2-(3,4- dichlorophenoxy) acetamido)piperidin-1- yl)butanoic acid hydrochloride 515.0 1.81-1.83 (m, 2 H),1.93 (bs, 2 H), 2.26-2.27 (m, 1 H), 3.13 (bs, 2 H), 3.50 (bs, 2 H), 3.87(bs, 1 H), 4.05 (bs, 2 H), 4.10-4.14 (m, 1 H), 4.54 (s, 2 H), 6.93-6.97(m, 3 H), 7.22 (d, J = 3.2 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 7.52 (d,J = 8.8 Hz, 1 H). 8.27 (d, J = 7.2 Hz, 1 H). 10.3 (bs, 1 H).

Example 542-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)-4-(3,4-dichlorophenoxy)butanoicacid

Step 1:

To a solution of 3, 4-dichlorophenol (1.0 g, 6.134 mmol, 1 equiv) in N,N-dimethylformamide (10 mL) was added anhydrous potassium carbonate(1.69 g, 12.269 mmol, 2.0 equiv) and ethyl 4-bromobutanoate (1.31 mL,9.202 mmol, 1.5 equiv). The reaction mixture was heated to 140° C. andstirred for 3 h. The progress of the reaction was monitored by TLC.After completion of reaction, the reaction mixture was allowed to coolto 27° C., the reaction mixture was diluted with water (50 mL),extracted with ethyl acetate (3×50 mL), the combined organics werewashed with brine (50 mL), dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to give the crudeproduct. The crude product was purified by silica gel columnchromatography using 10% ethyl acetate in hexanes as eluent to obtainthe title compound ethyl 4-(3,4-dichlorophenoxy)butanoate (1.5 g, 89%yield) as colourless liquid. LCMS (ES) m/z=277.0 [M+H]⁺. ¹H NMR (400MHz, CDCl3): δ ppm 1.25 (t, J=7.2 Hz, 3H), 2.06-2.13 (m, 2H), 2.49 (t,J=7.6 Hz, 2H), 3.97 (t, J=6.4 Hz, 2H), 4.12-4.17 (m, 2H), 6.73 (dd,J=8.8 Hz, 2.8 Hz, 1H), 6.97 (d, J=2.8 Hz, 1H). 7.30 (d, J=8.8 Hz, 1H).

Step 2:

To a solution of ethyl 4-(3,4-dichlorophenoxy)butanoate (0.5 g, 1.804mmol, 1.0 equiv) in dry tetrahydrofuran (20 mL) was added lithiumdiisopropylamide solution (2.0 M in THF/heptane/ethylbenzene) (1.35 mL,2.706 mmol, 1.5 equiv) slowly at −78° C. The reaction mixture wasstirred for another 1 h at −78° C. After 1 h, a solution of carbontetrabromide (0.89 g, 2.706 mmol, 1.5 equiv) in dry tetrahydrofuran (15mL) was added at −78° C., the mixture was gradually allowed to warm to27° C. and stirred for 2 h. The reaction mixture was quenched withsaturated aqueous solution of ammonium chloride (20 mL) and extractedwith ethyl acetate (3×30 mL). The combined organics were dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to give the crude product. The crude product was purified bysilica gel column chromatography using 7% ethyl acetate in hexane aseluent to obtain the title compound ethyl2-bromo-4-(3,4-dichlorophenoxy)butanoate (0.15 g, crude) as pale brownliquid. ¹H NMR (400 MHz, CDCl3): δ ppm 1.30 (t, J=6.8 Hz, 3H), 2.35-2.43(m, 1H), 2.49-2.58 (m, 1H), 4.04-4.13 (m, 2H), 4.20-4.28 (m, 2H),4.50-4.53 (m, 1H), 6.74 (dd, J=9.2 Hz, 3.2 Hz, 1H), 6.99 (d, J=2.4 Hz,1H), 7.32 (d, J=8.8 Hz, 1H).

Step 3:

To a stirred solution of ethyl 2-bromo-4-(3,4-dichlorophenoxy)butanoate(0.28 g, 0.786 mmol, 1.2 equiv) in N,N-dimethylformamide (5 mL) wereadded a 2-(4-chlorophenoxy)-N-(piperidin-4-yl)acetamide hydrochloride(0.2 g, 0.655 mmol, 1 equiv), and triethyl amine (0.27 mL, 1.965 mmol,3.0 equiv). The resulting mixture was stirred for 16 h at 27° C. Theprogress of the reaction was monitored by TLC. After completion ofreaction, the reaction mixture was quenched with water (50 mL) andextracted with ethyl acetate (3×50 mL), the combined organics werewashed with water (30 mL), brine (20 mL), dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to give thecrude product. The crude product was purified by silica gel columnchromatography (Combiflash) using 3% methanol in dichloromethane aseluent to obtain the title compound ethyl2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)-4-(3,4-dichlorophenoxy)butanoate(0.18 g, 51% yield) as pale brown gum. LCMS (ES) m/z=543.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.18 (t, J=7.2 Hz, 3H), 1.37-1.44 (m, 3H),1.66 (bs, 2H), 1.95-2.06 (m, 2H), 2.11-2.17 (m, 1H), 2.65-2.72 (m, 1H),2.83-2.84 (m, 1H), 3.39 (t, J=8.0 Hz, 1H), 3.55 (bs, 1H), 3.98-4.14 (m,4H), 4.42 (s, 2H), 6.91-6.95 (m, 3H), 7.19 (d, J=2.8 Hz, 1H) 7.31 (d,J=8.8 Hz, 2H), 7.49 (d, J=9.2 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H).

Step 4:

To a solution of ethyl2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)-4-(3,4-dichlorophenoxy)butanoate(0.17 g, 0.312 mmol, 1 equiv) in ethanol (5 mL) was added sodiumhydroxide (0.12 g, 0.3.125 mmol, 10 equiv) in 2 ml of water, the mixturewas heated to 50° C. and stirred for 3 h. The progress of the reactionwas monitored by TLC. After completion of reaction, the ethanol wasremoved by evaporation, the residue was diluted with water (5 mL),acidified with 1.5 M hydrochloric acid to pH 2 to 3. The aqueous layerwas extracted with ethyl acetate (3×30 mL). The combined organic layerswere washed with water (2×30 mL), dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to give the crudeproduct. The crude product was triturated with n-pentane and dried toobtain the title compound2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)-4-(3,4-dichlorophenoxy)butanoicacid (0.085 g, 53% yield) as off white solid. LCMS (ES) m/z=515.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 1.41-1.50 (m, 2H), 1.69 (bs,2H), 1.94-2.05 (m, 2H), 2.29 (d, J=9.6 Hz, 1H), 2.60 (bs, 1H), 2.77 (d,J=10.8 Hz, 1H), 2.85 (d, J=11.2 Hz, 1H) 3.38 (bs, 1H), 3.58 (bs, 1H),4.01-4.09 (m, 2H), 4.43 (s, 2H), 6.94 (d, J=8.8 Hz, 3H), 7.20 (d, J=2.4Hz, 1H), 7.31 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 1H) 7.93 (d, J=7.6Hz, 1H), 12.0 (bs, 1H).

TABLE 15 Cmpd LCMS m/z # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 54

2-(4-(2-(4- chlorophenoxy) acetamido) piperidin-1-yl)-4- (3,4-dichlorophenoxy) butanoic acid 515.1 1.41-1.50 (m, 2 H), 1.69 (bs, 2 H),1.94-2.05 (m, 2 H), 2.29 (d, J = 9.6 Hz, 1 H), 2.60 (bs, 1 H), 2.77 (d,J = 10.8 Hz, 1 H), 2.85 (d, J = 11.2 Hz, 1 H) 3.38 (bs, 1 H), 3.58 (bs,1 H), 4.01-4.09 (m, 2 H), 4.43 (s, 2 H), 6.94 (d, J = 8.8 Hz, 3 H), 7.20(d, J = 2.4 Hz, 1 H), 7.31 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 1H) 7.93 (d, J = 7.6 Hz, 1 H), 12.00 (bs, 1 H).

Example 55N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(4-(difluoromethoxy)phenoxy)acetamide

Step 1:

To a stirred solution of 1-(3-(4-chlorophenoxy)propyl)piperidin-4-aminehydrochloride (0.5 g, 1.64 mmol, 1.0 equiv.) in DCM (70 mL) was addedtriethyl amine (0.81 mL, 5.74 mmol, 3.5 equiv.) dropwise at 0° C. andwas stirred for 30 mins. Then compound chloro acetyl chloride (0.15 mL,1.96 mmol, 1.2 equiv.) was added dropwise at 0° C. Then reaction mixturewas stirred at room temperature for 16 h. After consumption of thestarting material (TLC, 5% MeOH in DCM), reaction mixture was dilutedwith DCM (100 mL), washed with ice cold water (2×50 mL), saturatedammonium chloride solution (50 mL) and water (50 mL). The combinedorganic layer was dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure. Crude was purified by flash columnchromatography using 6% methanol in dichloromethane to give2-chloro-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)acetamide (0.15g, 26.5% yield) as off white solid. LCMS (ES) m/z=345.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.35-1.43 (m, 2H), 1.68-1.71 (m, 2H), 1.82 (t,J=6.6 Hz, 2H), 1.96 (t, J=11.0 Hz, 2H), 2.38 (t, J=6.4 Hz, 2H), 2.77 (d,J=11.2 Hz, 2H), 3.50 (bs, 1H), 3.95-3.98 (m, 4H), 6.93 (d, J=8.8 Hz,2H), 7.29 (d, J=8.8 Hz, 2H), 8.07 (d, J=7.2 Hz, 1H).

Step 2:

To a stirred solution of2-chloro-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)acetamide (0.15g, 0.43 mmol, 1.0 equiv.) in acetonitrile (20 mL) was added caesiumcarbonate (0.35 g, 1.08 mmol, 2.5 equiv.) and compound4-(difluoromethoxy)phenol (0.08 mL, 0.65 mmol, 1.5 equiv.) at roomtemperature and then reaction mixture was stirred at 80° C. for 16 h.After consumption of the starting material (TLC, 5% MeOH in DCM),reaction mixture was concentrated under reduced pressure and to theresidue obtained was added water (5 mL), stirred for 15-20 mins and wasfiltered through sintered funnel. The solid obtained was washed withwater (10 mL), diethyl ether (3×10 mL) and n-pentane (2×10 mL), driedunder high vacuum to giveN-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(4-(difluoromethoxy)phenoxy)acetamide(0.136 g, 66.9% yield) as off white solid. LCMS (ES) m/z=469.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42-1.50 (m, 2H), 1.65-1.68 (m, 2H),1.82 (t, J=6.6 Hz, 2H), 1.94 (t, J=11.0 Hz, 2H), 2.37 (t, J=6.8 Hz, 2H),2.77-2.80 (m, 2H), 3.59-3.60 (m, 1H), 3.97 (t, J=6.2 Hz, 2H), 4.43 (s,2H), 6.88 (s, 0.25H), 6.92-6.97 (m, 4H), 7.07 (s, 0.25H), 7.10 (d, J=8.8Hz, 2H), 7.25 (s, 0.25H), 7.29 (d, J=8.8 Hz, 2H), 7.89 (d, J=8.0 Hz,1H).

The Compound of Example 56 was prepared generally according to theprocedure described above for Example 55.

TABLE 16 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 55

N-(1-(3-(4- chlorophenoxy) propyl)piperidin- 4-yl)-2-(4-(difluoromethoxy) phenoxy)acetamide 469.1 1.42-1.50 (m, 2 H), 1.65-1.68(m, 2 H), 1.82 (t, J = 6.6 Hz, 2H), 1.94 (t, J = 11.0 Hz, 2 H), 2.37 (t,J = 6.8 Hz, 2 H), 2.77-2.80 (m, 2 H), 3.59-3.60 (m, 1 H), 3.97 (t, J =6.2 Hz, 2 H), 4.43 (s, 2 H), 6.88 (s, 0.25 H), 6.92-6.97 (m, 4 H), 7.07(s, 0.25 H), 7.10 (d, J = 8.8 Hz, 2 H), 7.25 (s, 0.25 H), 7.29 (d, J =8.8 Hz, 2 H), 7.89 (d, J = 8.0 Hz, 1 H). 56

N-(1-(3-(4- chlorophenoxy) propyl)piperidin- 4-yl)-2-(4-cyclopropylphenoxy) acetamide 443.2 0.55 (d, J = 4.4 Hz, 2H), 0.85 (d, J= 7.2 Hz, 2 H), 1.42-1.50 (m, 2 H), 1.64-1.67 (m, 2 H), 1.82- 1.83 (m, 3H), 1.94 (t, J = 11.0 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2 H), 2.76-2.79 (m,2 H), 3.58- 3.60 (m, 1 H), 3.96 (t, J = 6.2 Hz, 2 H), 4.37 (s, 2H), 6.81(d, J = 8.4 Hz, 2 H), 6.93 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2 H), 7.83 (d, J = 8.0 Hz, 1 H).

Example 572-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-N-methylacetamide

Step 1:

To a stirred solution of tert-butyl(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)carbamate (0.1 g, 0.27mmol, 1.0 equiv.) in THF (10.0 mL) was added lithium aluminium hydride(1.0 M in THF) (0.81 g, 0.81 mmol, 3.0 equiv.) at 0° C. The reaction wasstirred at 70° C. for 3 h. After consumption of the starting material(TLC, 70% EtOAc in hexane), the reaction mixture was quenched by icecold water (3 mL) at 0° C. and was concentrated to give1-(3-(4-chlorophenoxy)propyl)-N-methylpiperidin-4-amine (0.08 g, crude)as pale yellow liquid. LCMS (ES) m/z=283.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ ppm—crude

Step 2:

To a stirred solution of1-(3-(4-chlorophenoxy)propyl)-N-methylpiperidin-4-amine (0.08 g, 0.28mmol, 1.0 equiv.) in DCM (10 mL) was added triethyl amine (0.12 mL, 0.84mmol, 3.0 equiv.) and compound 2-(4-chlorophenoxy)acetic acid (0.063 g,0.34 mmol, 1.2 equiv.) and T₃P (50% wt. in ethyl acetate) (0.42 mL, 0.70mmol, 2.5 equiv.) was added dropwise at 0° C. The reaction was stirredat room temperature for 16 h. After consumption of the starting material(TLC, 5% MeOH in DCM), the reaction mixture was diluted with DCM (50mL), and was washed with saturated sodium bicarbonate solution (2×10 mL)and water (2×10 mL). Combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated to get the crude. Crude waspurified by flash column chromatography using 3-4% methanol indichloromethane. It was again purified by prep HPLC (Analyticalconditions: Column: Inertsil ODS 3V (50 mm×2.1 mm×3 mic), Mobile phase(A): 0.1% Ammonia in water, Mobile phase (B): Acetonitrile Flow rate:0.7 mL/min, Compound RT: 4.89) to give2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-N-methylacetamide(0.014 g, 11.0% yield) as off white solid. LCMS (ES) m/z=451.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (d, J=10.8 Hz, 1H), 1.61-1.75 (m,3H), 1.82 (t, J=6.4 Hz, 2H), 1.89-1.96 (m, 2H), 2.38-2.40 (m, 2H), 2.69(s, 1H), 2.81 (s, 2H), 2.90 (d, J=10.8 Hz, 2H), 3.50-3.60 (m, 0.5H),3.96 (t, J=6.0 Hz, 2H), 4.10-4.20 (m, 0.6H), 4.81 (d, J=22.4 Hz, 2H),6.88-6.93 (m, 4H), 7.28 (d, J=8.8 Hz, 4H).

TABLE 17 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 57

2-(4- chlorophenoxy)- N-(1-(3-(4- chlorophenoxy) propyl)piperidin-4-yl)-N- methylacetamide 451.1 1.41 (d, J = 10.8 Hz, 1 H), 1.61- 1.75(m, 3H), 1.82 (t, J = 6.4 Hz, 2 H), 1.89-1.96 (m, 2 H), 2.38-2.40 (m, 2H), 2.69 (s, 1 H), 2.81 (s, 2H), 2.90 (d, J = 10.8 Hz, 2 H), 3.50-3.60(m, 0.5 H), 3.96 (t, J = 6.0 Hz, 2 H), 4.10-4.20 (m, 0.6 H), 4.81 (d, J= 22.4 Hz, 2 H), 6.88-6.93 (m, 4 H), 7.28 (d, J = 8.8 Hz, 4 H).

Example 584-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylicacid

Step 1:

To a solution of 1-(tert-butyl) 2-methyl4-oxopiperidine-1,2-dicarboxylate (0.6 g, 2.3 mmol, 1 equiv) in methanol(60 mL) at 0° C. was added portion wise ammonium acetate (1.79 g, 23.3mmol, 10 equiv) and maintained for 1 h at room temperature. After thatsodium cyanoborohydride (0.57 g, 9.2 mmol, 4 equiv) and acetic acid (2drops, catalytic) were added and maintained for 48 h at roomtemperature. After consumption of the starting material (tlc, 50% EtOAcin hexane), the reaction mixture was concentrated, diluted with 10%methanol in DCM (150 mL) and washed with 10% aqueous NaHCO₃ solution (20mL), cold water (20 mL), the organic layer dried over anhydrous sodiumsulphate, filtered and concentrated to obtain 1-(tert-butyl) 2-methyl4-aminopiperidine-1,2-dicarboxylate (0.5 g, crude, 99.6% yield) as offwhite solid. LCMS (ES) m/z=259.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δppm—crude.

Step 2:

To a solution of 1-(tert-butyl) 2-methyl4-aminopiperidine-1,2-dicarboxylate (0.5 g, 1.90 mmol, 1 equiv) in DCM(100.0 mL) at 0° C. was added triethylamine (0.66 mL, 4.7 mmol, 2.5equiv) and 2-(4-chlorophenoxy)acetic acid (0.43 g, 2.30 mmol, 1.2equiv). After stirring for 5 minutes, T₃P (50 wt. % in ethyl acetate)(2.85 mL, 4.70 mmol, 2.5 equiv) was added to the reaction mixture. Thenreaction mixture was allowed to stir at room temperature for 18 h. Afterconsumption of 1-(tert-butyl) 2-methyl4-aminopiperidine-1,2-dicarboxylate, the reaction mixture was dilutedwith DCM (150 mL) and washed with cold water (50 mL). The combinedorganic extract was washed with 10% aqueous NaHCO₃ solution (2×50 mL),water (50 mL) and dried over anhydrous sodium sulphate. The organiclayer was filtered and concentrated at rotavapor to give 1-(tert-butyl)2-methyl 4-(2-(4-chlorophenoxy)acetamido)piperidine-1,2-dicarboxylate(0.70 g, crude) as viscous liquid. LCMS (ES) m/z=327.2 [M+H]⁺ (Debocmass was observed). ¹H NMR (400 MHz, DMSO-d₆) δ ppm—crude.

Step 3:

To a solution of 1-(tert-butyl) 2-methyl4-(2-(4-chlorophenoxy)acetamido)piperidine-1,2-dicarboxylate (0.7 g, 1.6mmol, 1 equiv) in DCM (7.0 mL) at 0° C. was added 4M HCl in dioxane (7.0mL). Then reaction mixture was allowed to stir at room temperature for16 h. After consumption of 1-(tert-butyl) 2-methyl4-(2-(4-chlorophenoxy)acetamido)piperidine-1,2-dicarboxylate, thereaction mixture was concentrated at rotavapor and washed with n-pentane(2×10 mL) to give methyl4-(2-(4-chlorophenoxy)acetamido)piperidine-2-carboxylate hydrochloride(0.55 g, crude, 86.41% yield) as off white solid. LCMS (ES) m/z=327.0[M+H]⁺, free amine mass was observed. ¹H NMR (400 MHz, DMSO-d₆) δppm—crude.

Step 4:

To a solution of methyl4-(2-(4-chlorophenoxy)acetamido)piperidine-2-carboxylate hydrochloride(0.55 g, 1.5 mmol, 1 equiv) in Triethyl amine (0.84 mL, 6.0 mmol, 4.0equiv) at 0° C. was added 1-(3-bromopropoxy)-4-chlorobenzene (0.45 g,1.8 mmol, 1.2 equiv). Then reaction mixture was allowed to stir at 100°C. for 4 h. After consumption of methyl4-(2-(4-chlorophenoxy)acetamido)piperidine-2-carboxylate hydrochloride,the reaction mixture was diluted with 10% methanol in DCM (150 mL) andwashed with cold water (2×20 mL). The combined organic extract was driedover anhydrous sodium sulphate. The organic layer was filtered andconcentrated at rotavapor to give crude which was purified by flashchromatography using 1% to 50% ethyl acetate in hexane as an eluent toafford methyl4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylate(0.15 g, 20% yield) as off white solid. LCMS (ES) m/z=495.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.44-1.59 (m, 2H), 1.66-1.72 (m, 2H),1.79-1.96 (m, 2.5H), 2.02-2.20 (m, 1H), 2.21-2.30 (m, 0.5H), 2.58-2.64(m, 1.5H), 2.84-2.89 (m, 0.5H), 2.97-3.02 (m, 1H), 3.55 (s, 1H), 3.58(s, 2H), 3.59-3.68 (m, 0.5H), 3.80-3.82 (m, 0.5H), 3.95-4.01 (m, 2H),4.43 (s, 2H), 6.89-6.95 (m, 4H), 7.30 (t, J=9.4 Hz, 4H), 7.91 (d, J=8.0Hz, 0.5H), 7.97 (d, J=7.6 Hz, 0.5H).

Step 5:

To a stirred solution of methyl4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylate(0.15 g, 0.3 mmol, 1.0 equiv) in tetrahydrofuran (3 mL), water (0.75 mL)and lithium hydroxide monohydrate (0.05 g, 1.2 mmol, 4 equiv) were addedat room temperature and stirred for 36 h. Reaction mixture wasevaporated, resulting aqueous layer was acidified with 2 N HCl solutionat 0° C. and pH was maintained 5-6, obtained precipitate was filteredwashed with cold water (2×5 mL), diethyl ether (2×10 mL) pentane (2×10mL) and dried under vacuum to obtain4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylicacid (0.04 g, 27.58% yield) as off white solid. LCMS (ES) m/z=481.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.54 (m, 0.5H), 1.57-1.60(m, 0.5H), 1.68-1.77 (m, 1.5H), 1.84-1.94 (m, 3H), 2.65-2.71 (m, 1H),2.80 (bs, 0.5H), 2.90 (bs, 0.5H), 3.02 (bs, 1H), 3.16-3.19 (m, 1H), 3.53(s, 1H), 3.77-3.83 (m, 1.5H), 3.97 (s, 2H), 4.44 (s, 2H), 6.90-6.95 (m,4H), 7.30 (t, J=9.0 Hz, 4H), 7.95 (d, J=7.2 Hz, 0.6H), 8.08 (d, J=7.6Hz, 0.4H).

TABLE 18 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 58

4-(2-(4- chlorophenoxy) acetamido)-1-(3- (4- chlorophenoxy)propyl)piperidine- 2- carboxylic acid 481.4 1.49-1.54 (m, 0.5 H), 1.57-1.60 (m, 0.5 H), 1.68-1.77 (m, 1.5 H), 1.84-1.94 (m, 3 H), 2.65-2.71 (m,1 H), 2.80 (bs, 0.5 H), 2.90 (bs, 0.5 H), 3.02 (bs, 1 H), 3.16-3.19 (m,1 H), 3.53 (s, 1 H), 3.77-3.83 (m, 1.5 H), 3.97 (s, 2 H), 4.44 (s, 2 H),6.90-6.95 (m, 4 H), 7.30 (t, J = 9.0 Hz, 4 H), 7.95 (d, J = 7.2 Hz, 0.6H), 8.08 (d, J = 7.6 Hz, 0.4 H).

Example 594-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylicacid

Step 1:

Methyl4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylatewas purified by prep HPLC (Analytical conditions: Column: Inertsil ODS3V (250 mm×4.6 mm×5 mic), Mobile phase (A): 0.1% Ammonia in water,Mobile phase (B): Acetonitrile, Flow rate: 1.0 mL/min, compound RT(pair-1): 14.108 minutes, compound RT (pair −2): 17.987 minutes) to getZ14 (pair-1) and Z15 (pair −2). Z15 is used to next step (Methyl esterhydrolysis).

Step 2:

Compound 6 procedure reference is example of 5.(4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylicacid) (0.08 g, 83.33% yield) as white solid. LCMS (ES) m/z=481.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (d, J=9.2 Hz, 1H), 1.70-1.77 (m,2H), 1.86-1.95 (m, 3H), 2.63-2.70 (m, 2H), 2.85 (bs, 1H), 3.05-3.09 (m,1H), 3.60 (bs, 1H), 3.82-3.86 (m, 1H), 3.98 (t, J=6.2 Hz, 2H), 4.45 (s,2H), 6.93 (t, J=8.2 Hz, 4H), 7.30 (t, J=8.8 Hz, 4H), 7.98 (d, J=7.6 Hz,1H).

TABLE 19 LCMS m/z Cmpd # Structure Name [M + H]⁺ ¹H-NMR (400 MHz,DMSO-d₆) 59

4-(2-(4- chlorophenoxy) acetamido)- 1-(3-(4- chlorophenoxy)propyl)piperidine- 2-carboxylic acid 481.1 1.53 (d, J = 9.2 Hz, 1 H),1.70- 1.77 (m, 2 H), 1.86-1.95 (m, 3 H), 2.63-2.70 (m, 2 H), 2.85 (bs, 1H), 3.05-3.09 (m, 1 H), 3.60 (bs, 1 H), 3.82- 3.86 (m, 1 H), 3.98 (t, J= 6.2 Hz, 2 H), 4.45 (s, 2 H), 6.93 (t, J = 8.2 Hz, 4 H), 7.30 (t, J =8.8 Hz, 4 H), 7.98 (d, J = 7.6 Hz, 1 H).

Example 60: ATF4 Cell Based Assay

The ATF4 reporter assay measures the effect of Thapsigargin inducedcellular stress on ATF4 expression. For this reporter assay, a stablecell line was created by transfecting SH-SY5Y cells with a plasmidcontaining the NanoLuc® luciferase gene fused to the 5′-UTR of ATF4,under the control of the CMV promoter. The ATF4 5′-UTR contains two openreading frames which mediate the cellular stress-dependent translationof the reporter gene. Clones stably expressing the reporter constructwere isolated and selected based on the luminescence response tothapsigargin and inhibition of this signal by test compounds. Briefly,SH-SY5Y-ATF4-NanoLuc cells were challenged with Thapsigargin for 14-18hours to determine the stress effect with or without test compounds.

Cells were propagated in growth media consisting of 90% DMEM F12(InVitrogen #11320-033), 10% Fetal Bovine Serum (Gibco #10438-026), 5 mMGlutamax (Gibco #35050-061), 5 mM Hepes, (Gibco #15630-080), and 0.5mg/ml Geneticin (Gibco #10131-027). Cells were prepared for the assay byremoving all media from cells, washing the plated cells with phosphatebuffered saline, and detached by adding a solution comprised of 10%Tryple express solution (InVitrogen12604-021) and 90% enzyme-free celldissociation buffer HANKS base (Gibco 13150-016). The trypsin wasdeactivated by adding assay media comprised of 90% phenol-red free DMEMF12 (InVitrogen, 11039), 10% Fetal Bovine Serum (Gibco #10438-026), (5mM Glutamax (Gibco #35050-061), 5 mM Hepes, (Gibco #15630-080), and 0.5mg/ml Geneticin (Gibco #10131-027). Suspended cells were spun down at300 g for 5 min, the supernatant was removed and the cell pellet wassuspended in warm media (30-37° C.) comprised as above at (1e6 cell/ml).

Assay plates were prepared by adding 250 nL of compound stock solutionin 100% DMSO to each well, followed by dispensing 20 microliters/wellcell suspension to deliver 15-20k cell/well. Cells were incubated for 1hour at 37° C. Then, 5 μL of 1.5 μM or 1 μM of Thapsigargin (finalconcentration: 200-300 nM) was added to each well of cells. Assay platescontaining cells were incubated for 14-18 hours at 37° C.

The measurement of luciferase produced by the ATF4 constructs wasmeasured as follows. Aliquots of the Nano-Glo reagent (Nano-Glo®Luciferase Assay Substrate, Promega, N113, Nano-Glo® Luciferase AssayBuffer, Promega, N112 (parts of Nano-Glo® Luciferase Assay System,N1150) were brought to room temperature, the substrate and buffer weremixed according to manufacturer's instructions. The cell plates wereequilibrated to room temperature. 25 microliters/well of the mixedNano-Glo reagent were dispensed into assay wells and pulse spun tosettle contents and the plate was sealed with film. The plates wereincubated at room temperature for 1 hour before detecting luminescenceon an Envision plate reader.

Example 61—Capsule Composition

An oral dosage form for administering the present invention is producedby filing a standard two piece hard gelatin capsule with the ingredientsin the proportions shown in Table 2, below.

TABLE 20 INGREDIENTS AMOUNTS 2-(4-chlorophenoxy)-N-(1-(2-(4-  7 mgchlorophenoxy)acetyl)piperidin-4-yl)- acetamide (Compound of Example 1)Lactose 53 mg Talc 16 mg Magnesium Stearate  4 mg

Example 62—Injectable Parenteral Composition

An injectable form for administering the present invention is producedby stirring 1.7% by weight of2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)acetamide(Compound of Example 2) in 10% by volume propylene glycol in water.

Example 63 Tablet Composition

The sucrose, calcium sulfate dihydrate and a PERK inhibitor as shown inTable 4 below, are mixed and granulated in the proportions shown with a10% gelatin solution. The wet granules are screened, dried, mixed withthe starch, talc and stearic acid, screened and compressed into atablet.

TABLE 21 INGREDIENTS AMOUNTS 8-(2-(4-chlorophenoxy)acetyl)-3-(2-(4- 12mg  chlorophenoxy)ethyl)-1-oxa-3,8- diazaspiro[4.5]decan-2-one (Compoundof Example 3) calcium sulfate dihydrate 30 mg  sucrose 4 mg starch 2 mgtalc 1 mg stearic acid 0.5 mg  

Biological Activity

Compounds of the invention are tested for activity against ATF4translation in the above assay.

The compounds of Examples 1 and 3 to 8 were tested generally accordingto the above ATF4 cell based assay and in a set of two or moreexperimental runs exhibited an average ATF4 pathway inhibitory activity(IC₅₀)<300 nM.

The compound of Example 1 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 75.86nM.

The compound of Example 2 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀)<4000 nM.

The compounds of Examples 9 to 26, 28, 30 to 38, 41 to 48, 50 to 55, and57 to 59 were tested generally according to the above ATF4 cell basedassay and in a set of two or more experimental runs exhibited an averageATF4 pathway inhibitory activity (IC₅₀)<1,000 nM.

The compounds of Examples 27, 29, 39, 40, 49, and 56 were testedgenerally according to the above ATF4 cell based assay and in a set oftwo or more experimental runs exhibited an average ATF4 pathwayinhibitory activity (IC₅₀)>1,000 nM.

The compound of Example 11 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 32 nM.

The compound of Example 17 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 76.8 nM.

The compound of Example 24 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 200.6nM.

The compound of Example 30 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 110.5nM.

The compound of Example 37 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 98.7 nM.

The compound of Example 43 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 58.4 nM.

The compound of Example 50 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 93.9 nM.

The compound of Example 57 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 61.2 nM.

The compound of Example 59 was tested generally according to the aboveATF4 cell based assay and in a set of two or more experimental runsexhibited an average ATF4 pathway inhibitory activity (IC₅₀) of 172.5nM.

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Protein synthesis and its    control in neuronal cells with a focus on vanishing white matter    disease. Biochem Soc Trans 37:1298-20 1310.-   24. Costa-Mattioli M. Gobert D., Harding H., Herdy B. Azzi M.,    Bruno M. et al, 2005. Translational control of hippocampal synaptic    plasticity and memory by the eIF2n kinase GCN2. Nature    436:1166-1173.-   25. Costa-Mattioli M., Gobert D., Stern E., Garnache K., Colina R I,    Cuello C., Sossin W., Kaufman R., Pelletier J., Rosenblum et al.    2007. eIF2n phosphorylation bidirectionally regulates the switch    from short to long term synaptic plasticity and memory. Cell 25 129:    195-206.-   26. Zhu P. J, Huan W., Kalikulov D., Yoo J. W., Placzek A. N.,    Stoica L, Zhou H., Bell J. C., Frielander M. J., Krnjevic K.,    Noebels J. L., Costa-Mattioli M. 2011. Suppression of PKR promotes    network excitability and enhanced cognition by interferon-7-mediated    disinhibition. Cell 147: 1384-1396.-   27. Borck G., Shin B. 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While the preferred embodiments of the invention are illustrated by theabove, it is to be understood that the invention is not limited to theprecise instructions herein disclosed and that the right to allmodifications coming within the scope of the following claims isreserved.

1. A compound according to Formula (III):

wherein: L² is selected from: a bond, —NH—, —O—, —S—, —S(O)—, —S(O)₂—,substituted or unsubstituted C₁₋₈alkylene or substituted orunsubstituted C₁₋₆heteroalkylene, or L² is further taken together with Bto form heterocycloalkyl; L³ is selected from: a bond, —NH—, —O—, —S—,—S(O)—, —S(O)₂—, substituted or unsubstituted C₁₋₆alkylene orsubstituted or unsubstituted C₁₋₆heteroalkylene, or L³ is further takentogether with A to form heterocycloalkyl; L¹ is selected from: a bond,—NH—, —C(R⁷)—, —O—, —S—, —S(O)—, —S(O)₂—, substituted or: unsubstitutedC₁₋₆alkylene and substituted or unsubstituted C₁₋₆heteroalkylene; R¹ isCH—, or R¹ is C— and taken together with R³ and the nitrogen to which R³is attached, and optionally from 1 to 3 additional heteroatoms, to forma heterocycloalkyl, which is optionally substituted with from 1 to 5substituents independently selected from: fluoro, chloro, C₁₋₆alkyl,C₁₋₆alkyl substituted 1 to 6 times by fluoro, C₁₋₄alkoxy, C₁₋₄alkoxysubstituted 1 to 6 times by fluoro, oxo, and —NH₂; R³, R⁵ and R⁶ and areindependently hydrogen, fluoro, chloro, bromo, iodo, —OCH₃, —OCH₂Ph,—C(O)Ph, —CH₃, —CF₃, —CN, —S(O)CH₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—C(O)CH₃, —CH(CH₃)₂, —CCH, —CH₂CCH, —SO₃H, —SO₂NH₂, —NHC(O)NH₂,—NHC(O)H, —NHOH, —OCF₃, —OCHF₂, substituted or unsubstitutedC₁₋₆alkylene, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, provided R³ is absent when Z is a nitrogen linkedheteroaryl; R² and R⁴ are independently NR⁸, O, or S; R⁷ is selectedfrom: ═NR⁸, ═O, and ═S; R⁸ is selected from: hydrogen, C₁₋₆alkyl andC₁₋₆alkyl substituted 1 to 6 times by fluoro; R⁹ is selected from:hydrogen, fluoro, chloro, bromo, iodo, —OH, C₁₋₃alkyl and C₁₋₃alkylsubstituted with from 1 to 3 substituents independently selected from:fluoro, oxo, —OH, and —NH₂; A and B are independently aryl orheteroaryl; z2 and z4 are independently 0 or 1; z5 and z6 areindependently an integer from 0 to 5; X is absent or present asC₁₋₂alkyl or C₁₋₂alkyl substituted 1 to 2 times by fluoro, where thedotted lines represent optional bonds of the alkyl chain of X; Y isabsent or present as C₁₋₂alkyl or C₁₋₂alkyl substituted 1 to 2 times byfluoro, where the dotted lines represent optional bonds of the alkylchain of Y; and Z is nitrogen or a nitrogen linked heteroaryl; or a saltthereof including a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1 represented by the following Formula (IV):

wherein: L¹² and L¹³ are independently: —CH₂—O—, —O—CH₂—, —CH₂—CH₂—O—,—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O— and —O—CH₂—CH₂—CH₂—; L¹¹ is selected from:a bond, —CH₂— and —C(O)—; R¹¹ is CH— and R¹³ is hydrogen, or R¹ 1 is C—and taken together with R¹³ and the nitrogen to which R¹³ is attachedform an oxazolidine, which is optionally substituted by oxo; R¹⁵ and R¹⁶are independently hydrogen or chloro; R¹² and R¹⁴ are O; R¹⁹ is selectedfrom: hydrogen, fluoro, chloro, —OH, C₁₋₃alkyl and C₁₋₃alkyl substitutedwith from 1 to 3 substituents independently selected from: fluoro, oxo,and —OH; z¹² and z¹⁴ are independently 0 or 1; z¹⁵ and z¹⁶ areindependently an integer from 0 to 5; X¹ is absent or present asC₁₋₂alkyl or C₁₋₂alkyl substituted 1 to 2 times by fluoro, where thedotted lines represent optional bonds of the alkyl chain of X; and Y¹ isabsent or present as C₁₋₂alkyl or C₁₋₂alkyl substituted 1 to 2 times byfluoro, where the dotted lines represent optional bonds of the alkylchain of Y; or a salt thereof including a pharmaceutically acceptablesalt thereof.
 3. The compound of claim 1 selected from:2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-4-yl)acetamide;8-(2-(4-chlorophenoxy)acetyl)-3-(2-(4-chlorophenoxy)ethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)acetamide;N-(2-(4-chlorophenoxy)ethyl)-1-(3-(4-chlorophenoxy)propanoyl)piperidine-4-carboxamide;2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propanoyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-((1-(2-(4-chlorophenoxy)acetyl)piperidin-4-yl)methyl)acetamide; N-(1-(2-((5-chloroisothiazol-3-y)oxy)ethyl)piperidin-4-y)-2-(4-chlorophenoxy)acetamide;N-(1-(3-((5-chloroisothiazol-3-y)oxy)propyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide;2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide;(R)-2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide;(S)-2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-fluoropropyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(2-(3-(4-chlorophenoxy)-2-hydroxypropyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-methoxypropyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(3-((6-chloropyridin-3-yl)oxy)propyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(2-(3-(4-chlorophenoxy)propyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide;N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-y)-2-((5-chloropyridin-2-yl)oxy)acetamide;2-(4-chlorophenoxy)-N-(1-(3-((5-chloropyridin-2-yl)oxy)propyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(3-(3,4-dichlorophenoxy)propyl)piperidin-4-yl)acetamide;4-(2-((4-chlorophenoxy)methyl)-1H-imidazol-1-yl)-1-(3-(4-chlorophenoxy)propyl)piperidine;2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)-3-methylpiperidin-4-yl)acetamide;N-(4-chlorophenethyl)-1-(2-(4-chlorophenoxy)acetyl)piperidine-4-carboxamide;2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propanoyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(4-(4-chlorophenyl)butanoyl)-3-fluoropiperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)acetamide;2-(4-chlorophenoxy)-N-(2-(1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)ethyl)acetamide;N-((1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)methyl)-2-((6-chloropyridin-3-yl)oxy)acetamide;2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)-3-fluoropiperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(2-(2-(4-chlorophenoxy)acetyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide;2-(4-chlorophenoxy)-N-(1-((1R,2R)-2-(4-chlorophenoxy)cyclopropane-1-carbonyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-((1R,2S)-2-(4-chlorophenoxy)cyclopropane-1-carbonyl)piperidin-4-yl)acetamide;N-(1-((1S,2R)-2-(4-chlorobenzyl)cyclopropane-1-carbonyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide;N-(1-((1R,2R)-2-(4-chlorobenzyl)cyclopropane-1-carbonyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide;2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenyl)cyclopropane-1-carbonyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(4-(4-chlorophenyl)butanoyl)piperidin-4-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-methylpiperidin-4-yl)acetamide;N,1-bis(2-(4-chlorophenoxy)ethyl)piperidine-4-carboxamide;N-(2-(4-chlorophenoxy)ethyl)-1-(3-(4-chlorophenoxy)propyl)piperidine-4-carboxamide;2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-hydroxypiperidin-4-yl)acetamide;6-chloro-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)chromane-2-carboxamide;N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-((6-chloropyridin-3-yl)oxy)acetamide;N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(3,4-dichlorophenoxy)acetamide;N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(2,4-dichlorophenoxy)acetamide;2-(4-chlorophenoxy)-N-((1R,5S)-8-(3-(4-chlorophenoxy)propyl)-8-azabicyclo[3.2.1]octan-3-yl)acetamide;2-(4-chlorophenoxy)-N-(1-(2-(3,4-dichlorophenoxy)ethyl)-3-fluoropiperidin-4-yl)acetamide;N-(1-(2-(4-chlorophenoxy)ethyl)-3-fluoropiperidin-4-yl)-2-(3,4-dichlorophenoxy)acetamide;2-(4-chlorophenoxy)-N-((1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)methyl)acetamide;2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-fluoropiperidin-4-yl)acetamide;4-(4-chlorophenoxy)-2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)butanoicacid;2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)-2-oxopiperidin-4-yl)acetamide;4-(4-chlorophenoxy)-2-(4-(2-(3,4-dichlorophenoxy)acetamido)piperidin-1-yl)butanoicacid;2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)-4-(3,4-dichlorophenoxy)butanoicacid;N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(4-(difluoromethoxy)phenoxy)acetamide;N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(4-cyclopropylphenoxy)acetamide;2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-N-methylacetamide;4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylicacid; and4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylicacid; or a salt thereof including a pharmaceutically acceptable saltthereof.
 4. A pharmaceutical composition comprising a compound accordingto claim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.
 5. A method of treating a diseaseselected from: cancer, pre-cancerous syndromes, Alzheimer's disease,spinal cord injury, traumatic brain injury, ischemic stroke, stroke,diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-JakobDisease, and related prion diseases, progressive supranuclear palsy,amyotrophic lateral sclerosis, myocardial infarction, cardiovasculardisease, inflammation, fibrosis, chronic and acute diseases of theliver, chronic and acute diseases of the lung, chronic and acutediseases of the kidney, chronic traumatic encephalopathy (CTE),neurodegeneration, dementia, cognitive impairment, atherosclerosis,ocular diseases, in organ transplantation and arrhythmias, in a mammalin need thereof, which comprises administering to such mammal atherapeutically effective amount of a compound as described in claim 1or a pharmaceutically acceptable salt thereof.
 6. The method of claim 5wherein the mammal is a human. 7-8. (canceled)
 9. The method accordingto claim 5 wherein said cancer is selected from: brain (gliomas),glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonanasyndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, headand neck, kidney, lung, liver, melanoma, ovarian, pancreatic,adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinarcell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid.10-11. (canceled)
 12. The method of inhibiting the ATF4 pathway in amammal in need thereof, which comprises administering to such mammal atherapeutically effective amount of a compound as described in claim 1or a pharmaceutically acceptable salt thereof.
 13. The method of claim12 wherein the mammal is a human.
 14. A method of treating cancer in amammal in need thereof, which comprises: administering to such mammal atherapeutically effective amount of a) a compound as described in claim1 or a pharmaceutically acceptable salt thereof; and b) at least oneanti-neoplastic agent.
 15. The method claim 14, wherein the at least oneanti-neoplastic agent is selected from the group consisting of:anti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormonal analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis, inhibitors, immunotherapeutic agents, proapoptotic agents,cell cycle signaling inhibitors, proteasome inhibitors, and inhibitorsof cancer metabolism.
 16. A pharmaceutical combination comprising: a) acompound as described in claim 1 or a pharmaceutically acceptable saltthereof; and b) at least one anti-neoplastic agent.
 17. (canceled) 18.The method according to claim 5 wherein said cancer is selected from:breast cancer, inflammatory breast cancer, ductal carcinoma, lobularcarcinoma, colon cancer, pancreatic cancer, insulinomas, adenocarcinoma,ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma,glucagonoma, skin cancer, melanoma, metastatic melanoma, lung cancer,small cell lung cancer, non-small cell lung cancer, squamous cellcarcinoma, adenocarcinoma, large cell carcinoma, brain (gliomas),glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonanasyndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor,Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head andneck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma,ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma,glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant celltumor of bone, thyroid, lymphoblastic T cell leukemia, chronicmyelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia,acute lymphoblastic leukemia, acute myelogenous leukemia, chronicneutrophilic leukemia, acute lymphoblastic T cell leukemia,plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia,multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acutemegakaryocytic leukemia, promyelocytic leukemia, erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, vulval cancer,cervical cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor), neuroendocrine cancers and testicularcancer.
 19. The method of claim 18 wherein the mammal is a human.
 20. Aprocess for preparing a pharmaceutical composition containing apharmaceutically acceptable excipient and an effective amount of acompound as described in claim 1 or a pharmaceutically acceptable saltthereof, which process comprises bringing the compound or apharmaceutically acceptable salt thereof into association with apharmaceutically acceptable excipient.
 21. The method according to claim5 wherein said pre-cancerous syndrome is selected from: cervicalintraepithelial neoplasia, monoclonal gammapathy of unknown significance(MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions,skin nevi (pre-melanoma), prostatic intraepithleial (intraductal)neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps andsevere hepatitis or cirrhosis.
 22. (canceled)
 23. A method of treatingocular diseases in a human in need thereof, which comprisesadministering to such human a therapeutically effective amount of acompound as described in claim 1 or a pharmaceutically acceptable saltthereof.
 24. A method according to claim 23 wherein the ocular diseaseis selected from: rubeosis irides; neovascular glaucoma; pterygium;vascularized glaucoma filtering blebs; conjunctival papilloma; choroidalneovascularization associated with age-related macular degeneration(AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema;retinal neovascularization due to diabetes; age-related maculardegeneration (AMD); macular degeneration (AMD); ocular ischemic syndromefrom carotid artery disease; ophthalmic or retinal artery occlusion;sickle cell retinopathy; retinopathy of prematurity; Eale's Disease; andVonHippel-Lindau syndrome.
 25. A method according to claim 23 whereinthe ocular disease is selected form: age-related macular degeneration(AMD) and macular degeneration.
 26. A method of treatingneurodegeneration in a human in need thereof, which comprisesadministering to such human a therapeutically effective amount of acompound of Formula I, as described in claim 1 or a pharmaceuticallyacceptable salt thereof.
 27. A method of preventing organ damage duringthe transportation of organs for transplantation, which comprises addinga compound as described in claim 1 or a pharmaceutically acceptable saltthereof, to a solution housing the organ during transportation. 28.-35.(canceled)